Key clinical point: Unilateral pain, fewer failed preventives, good response to triptans, and medication overuse at baseline were associated with a persistent positive response to galcanezumab during the first 3 months of therapy in patients with chronic migraine.

Major finding: Overall, 41.7% of patients had a persistent 3-month 50% responder rate in headache days of at least moderate intensity. Responders vs. nonresponders had lower number of failed preventives (odds ratio [OR] 0.733; P = .041), frequent unilateral pain (OR 3.686; P = .041), medication overuse at baseline (OR 4.575; P = .012), and good response to triptans (OR 3.248; P = .028).

Study details: This observational study included 156 adult patients with chronic migraine from the GARLIT study who had a galcanezumab prescription.

Disclosures: This study was funded by Campus Bio-Medico University. Some investigators including the lead author received grants, travel expenses, and honoraria for advisory boards, speaker panels, or clinical investigation studies from various pharmaceutical companies.

Source: Vernieri F et al. Eur J Neurol. 2021 (Nov 26). Doi: 10.1111/ene.15197.

Key clinical point: Unilateral pain, fewer failed preventives, good response to triptans, and medication overuse at baseline were associated with a persistent positive response to galcanezumab during the first 3 months of therapy in patients with chronic migraine.

Major finding: Overall, 41.7% of patients had a persistent 3-month 50% responder rate in headache days of at least moderate intensity. Responders vs. nonresponders had lower number of failed preventives (odds ratio [OR] 0.733; P = .041), frequent unilateral pain (OR 3.686; P = .041), medication overuse at baseline (OR 4.575; P = .012), and good response to triptans (OR 3.248; P = .028).

Study details: This observational study included 156 adult patients with chronic migraine from the GARLIT study who had a galcanezumab prescription.

Disclosures: This study was funded by Campus Bio-Medico University. Some investigators including the lead author received grants, travel expenses, and honoraria for advisory boards, speaker panels, or clinical investigation studies from various pharmaceutical companies.

Source: Vernieri F et al. Eur J Neurol. 2021 (Nov 26). Doi: 10.1111/ene.15197.

Key clinical point: Unilateral pain, fewer failed preventives, good response to triptans, and medication overuse at baseline were associated with a persistent positive response to galcanezumab during the first 3 months of therapy in patients with chronic migraine.

Major finding: Overall, 41.7% of patients had a persistent 3-month 50% responder rate in headache days of at least moderate intensity. Responders vs. nonresponders had lower number of failed preventives (odds ratio [OR] 0.733; P = .041), frequent unilateral pain (OR 3.686; P = .041), medication overuse at baseline (OR 4.575; P = .012), and good response to triptans (OR 3.248; P = .028).

Study details: This observational study included 156 adult patients with chronic migraine from the GARLIT study who had a galcanezumab prescription.

Disclosures: This study was funded by Campus Bio-Medico University. Some investigators including the lead author received grants, travel expenses, and honoraria for advisory boards, speaker panels, or clinical investigation studies from various pharmaceutical companies.

Source: Vernieri F et al. Eur J Neurol. 2021 (Nov 26). Doi: 10.1111/ene.15197.

Key clinical point: Lasmiditan was associated with mild-to-moderate central nervous system (CNS)-related adverse events (AE), mostly transient in duration.

Major finding: Treatment-emergent serious AEs occurred in 0.4%, 0.2%, and 0.4% of patients treated with placebo, 100 mg lasmiditan, and 200 mg lasmiditan, respectively. The most common treatment-emergent AEs with lasmiditan were dizziness, nausea, paresthesia, fatigue, somnolence, and vertigo, with mostly mild-to-moderate severity. No deaths were reported.

Study details: Findings are from safety analysis of the phase 3 CENTURION trial that assessed 4,494 attacks across 1,471 patients with migraine with and without aura who were randomly assigned to either 200 mg lasmiditan or 100 mg lasmiditan for 4 attacks or placebo for 3 attacks and 50 mg lasmiditan for the third/fourth attack.

Disclosures: This study was sponsored by Eli Lilly and Company. Some investigators, including the lead author, reported receiving research grants, institutional payments, or fees for advisory boards and scientific lecturing; being an employee of; owning shares in; or consulting for various sources, including Eli Lilly and Company.

Source: Tassorelli C et al. J Headache Pain. 2021;22:132 (Nov 6). Doi: 10.1186/s10194-021-01343-2.

Key clinical point: Lasmiditan was associated with mild-to-moderate central nervous system (CNS)-related adverse events (AE), mostly transient in duration.

Major finding: Treatment-emergent serious AEs occurred in 0.4%, 0.2%, and 0.4% of patients treated with placebo, 100 mg lasmiditan, and 200 mg lasmiditan, respectively. The most common treatment-emergent AEs with lasmiditan were dizziness, nausea, paresthesia, fatigue, somnolence, and vertigo, with mostly mild-to-moderate severity. No deaths were reported.

Study details: Findings are from safety analysis of the phase 3 CENTURION trial that assessed 4,494 attacks across 1,471 patients with migraine with and without aura who were randomly assigned to either 200 mg lasmiditan or 100 mg lasmiditan for 4 attacks or placebo for 3 attacks and 50 mg lasmiditan for the third/fourth attack.

Disclosures: This study was sponsored by Eli Lilly and Company. Some investigators, including the lead author, reported receiving research grants, institutional payments, or fees for advisory boards and scientific lecturing; being an employee of; owning shares in; or consulting for various sources, including Eli Lilly and Company.

Source: Tassorelli C et al. J Headache Pain. 2021;22:132 (Nov 6). Doi: 10.1186/s10194-021-01343-2.

Key clinical point: Lasmiditan was associated with mild-to-moderate central nervous system (CNS)-related adverse events (AE), mostly transient in duration.

Major finding: Treatment-emergent serious AEs occurred in 0.4%, 0.2%, and 0.4% of patients treated with placebo, 100 mg lasmiditan, and 200 mg lasmiditan, respectively. The most common treatment-emergent AEs with lasmiditan were dizziness, nausea, paresthesia, fatigue, somnolence, and vertigo, with mostly mild-to-moderate severity. No deaths were reported.

Study details: Findings are from safety analysis of the phase 3 CENTURION trial that assessed 4,494 attacks across 1,471 patients with migraine with and without aura who were randomly assigned to either 200 mg lasmiditan or 100 mg lasmiditan for 4 attacks or placebo for 3 attacks and 50 mg lasmiditan for the third/fourth attack.

Disclosures: This study was sponsored by Eli Lilly and Company. Some investigators, including the lead author, reported receiving research grants, institutional payments, or fees for advisory boards and scientific lecturing; being an employee of; owning shares in; or consulting for various sources, including Eli Lilly and Company.

Source: Tassorelli C et al. J Headache Pain. 2021;22:132 (Nov 6). Doi: 10.1186/s10194-021-01343-2.

Key clinical point: Greater occipital nerve (GON) blockade with local anesthetics reduced the severity and duration of headaches in patients with episodic migraine without aura, with the headache frequency reducing significantly among patients receiving lidocaine alone or in combination with triamcinolone.

Major finding: GON block with triamcinolone, lidocaine, lidocaine+triamcinolone, or only normal saline significantly reduced the severity (P < .001) and duration (P = .001) of headaches, with no injection being superior to placebo. Headache frequency reduced in patients who received lidocaine (5.81 attacks per month; 95% CI of the difference −2.52 to −9.09) and lidocaine+triamcinolone (5.69 attacks per month; 95% CI of the difference −1.11 to −10.27).

Study details: This placebo-controlled clinical trial randomly assigned 55 adult patients with episodic migraine without aura to triamcinolone (n = 10), lidocaine (n = 16), lidocaine+triamcinolone (n = 13), or normal saline only (n = 16) groups.

Disclosures: This work was supported by the Iranian Center of Neurological Research in affiliation with Tehran University of Medical Sciences. The authors declared no conflict of interests.

Source: Malekian N et al. Cephalalgia. 2021 (Nov 17). Doi: 10.1177/03331024211058182.

Key clinical point: Greater occipital nerve (GON) blockade with local anesthetics reduced the severity and duration of headaches in patients with episodic migraine without aura, with the headache frequency reducing significantly among patients receiving lidocaine alone or in combination with triamcinolone.

Major finding: GON block with triamcinolone, lidocaine, lidocaine+triamcinolone, or only normal saline significantly reduced the severity (P < .001) and duration (P = .001) of headaches, with no injection being superior to placebo. Headache frequency reduced in patients who received lidocaine (5.81 attacks per month; 95% CI of the difference −2.52 to −9.09) and lidocaine+triamcinolone (5.69 attacks per month; 95% CI of the difference −1.11 to −10.27).

Study details: This placebo-controlled clinical trial randomly assigned 55 adult patients with episodic migraine without aura to triamcinolone (n = 10), lidocaine (n = 16), lidocaine+triamcinolone (n = 13), or normal saline only (n = 16) groups.

Disclosures: This work was supported by the Iranian Center of Neurological Research in affiliation with Tehran University of Medical Sciences. The authors declared no conflict of interests.

Source: Malekian N et al. Cephalalgia. 2021 (Nov 17). Doi: 10.1177/03331024211058182.

Key clinical point: Greater occipital nerve (GON) blockade with local anesthetics reduced the severity and duration of headaches in patients with episodic migraine without aura, with the headache frequency reducing significantly among patients receiving lidocaine alone or in combination with triamcinolone.

Major finding: GON block with triamcinolone, lidocaine, lidocaine+triamcinolone, or only normal saline significantly reduced the severity (P < .001) and duration (P = .001) of headaches, with no injection being superior to placebo. Headache frequency reduced in patients who received lidocaine (5.81 attacks per month; 95% CI of the difference −2.52 to −9.09) and lidocaine+triamcinolone (5.69 attacks per month; 95% CI of the difference −1.11 to −10.27).

Study details: This placebo-controlled clinical trial randomly assigned 55 adult patients with episodic migraine without aura to triamcinolone (n = 10), lidocaine (n = 16), lidocaine+triamcinolone (n = 13), or normal saline only (n = 16) groups.

Disclosures: This work was supported by the Iranian Center of Neurological Research in affiliation with Tehran University of Medical Sciences. The authors declared no conflict of interests.

Source: Malekian N et al. Cephalalgia. 2021 (Nov 17). Doi: 10.1177/03331024211058182.

Key clinical point: Intranasal ketorolac was not inferior to intravenous ketorolac in reducing pain intensity 60 min postmedication in children with migraine headaches of moderate-to-severe pain intensity.

Major finding: The difference in mean pain reduction at 60 min between intranasal and intravenous ketorolac groups was 0.2 (95% CI −0.9 to 1.3), with intranasal ketorolac being noninferior to intravenous ketorolac (P < .001). No serious adverse events were reported.

Study details: Findings are from a phase 3 clinical trial including 59 children (age 8-17 years) with migraine headache of moderate-to-severe pain intensity requiring any intravenous analgesic. They were randomly assigned to receive either intranasal ketorolac (1 mg/kg) or intravenous ketorolac (0.5 mg/kg).

Disclosures: This study was funded by the Columbia University’s CTSA grant from NCATS/NIH and Migraine Research Foundation. The authors declared no conflict of interests.

Source: Tsze DS et al. Acad Emerg Med. 2021 (Nov 25). Doi: 10.1111/acem.14422.

Key clinical point: Intranasal ketorolac was not inferior to intravenous ketorolac in reducing pain intensity 60 min postmedication in children with migraine headaches of moderate-to-severe pain intensity.

Major finding: The difference in mean pain reduction at 60 min between intranasal and intravenous ketorolac groups was 0.2 (95% CI −0.9 to 1.3), with intranasal ketorolac being noninferior to intravenous ketorolac (P < .001). No serious adverse events were reported.

Study details: Findings are from a phase 3 clinical trial including 59 children (age 8-17 years) with migraine headache of moderate-to-severe pain intensity requiring any intravenous analgesic. They were randomly assigned to receive either intranasal ketorolac (1 mg/kg) or intravenous ketorolac (0.5 mg/kg).

Disclosures: This study was funded by the Columbia University’s CTSA grant from NCATS/NIH and Migraine Research Foundation. The authors declared no conflict of interests.

Source: Tsze DS et al. Acad Emerg Med. 2021 (Nov 25). Doi: 10.1111/acem.14422.

Key clinical point: Intranasal ketorolac was not inferior to intravenous ketorolac in reducing pain intensity 60 min postmedication in children with migraine headaches of moderate-to-severe pain intensity.

Major finding: The difference in mean pain reduction at 60 min between intranasal and intravenous ketorolac groups was 0.2 (95% CI −0.9 to 1.3), with intranasal ketorolac being noninferior to intravenous ketorolac (P < .001). No serious adverse events were reported.

Study details: Findings are from a phase 3 clinical trial including 59 children (age 8-17 years) with migraine headache of moderate-to-severe pain intensity requiring any intravenous analgesic. They were randomly assigned to receive either intranasal ketorolac (1 mg/kg) or intravenous ketorolac (0.5 mg/kg).

Disclosures: This study was funded by the Columbia University’s CTSA grant from NCATS/NIH and Migraine Research Foundation. The authors declared no conflict of interests.

Source: Tsze DS et al. Acad Emerg Med. 2021 (Nov 25). Doi: 10.1111/acem.14422.

Key clinical point: A 140 mg dose of erenumab monthly was well tolerated and showed sustained efficacy over 2 years in patients with episodic migraine who failed 2-4 prior migraine preventive treatments.

Major finding: At week 112, the proportion of patients achieving ³50%, ³75%, and 100% reduction in monthly migraine days from baseline was 57.2%, 30.6%, and 16.2%, respectively. Overall, 86.3% of patients experienced treatment-emergent adverse events, the most common being nasopharyngitis, influenza, and back pain. No deaths or new safety signals were reported.

Study details: Findings are 2-year follow-up results of the phase 3b LIBERTY study including 240 patients with episodic migraine who failed 2-4 prior prophylactic treatments, completed placebo-controlled double-blind treatment phase, and were enrolled in the 3-year open-label extension phase with 140 mg erenumab monthly.

Disclosures: This study was supported by Novartis Pharma, Switzerland. Some investigators reported receiving grants and fees from, owning stocks in, or being an employee of various pharmaceutical companies, including Novartis.

Source: Ferrari MD et al. J Neurol Neurosurg Psychiatry. 2021 (Nov 29). Doi: 10.1136/jnnp-2021-327480.

Key clinical point: A 140 mg dose of erenumab monthly was well tolerated and showed sustained efficacy over 2 years in patients with episodic migraine who failed 2-4 prior migraine preventive treatments.

Major finding: At week 112, the proportion of patients achieving ³50%, ³75%, and 100% reduction in monthly migraine days from baseline was 57.2%, 30.6%, and 16.2%, respectively. Overall, 86.3% of patients experienced treatment-emergent adverse events, the most common being nasopharyngitis, influenza, and back pain. No deaths or new safety signals were reported.

Study details: Findings are 2-year follow-up results of the phase 3b LIBERTY study including 240 patients with episodic migraine who failed 2-4 prior prophylactic treatments, completed placebo-controlled double-blind treatment phase, and were enrolled in the 3-year open-label extension phase with 140 mg erenumab monthly.

Disclosures: This study was supported by Novartis Pharma, Switzerland. Some investigators reported receiving grants and fees from, owning stocks in, or being an employee of various pharmaceutical companies, including Novartis.

Source: Ferrari MD et al. J Neurol Neurosurg Psychiatry. 2021 (Nov 29). Doi: 10.1136/jnnp-2021-327480.

Key clinical point: A 140 mg dose of erenumab monthly was well tolerated and showed sustained efficacy over 2 years in patients with episodic migraine who failed 2-4 prior migraine preventive treatments.

Major finding: At week 112, the proportion of patients achieving ³50%, ³75%, and 100% reduction in monthly migraine days from baseline was 57.2%, 30.6%, and 16.2%, respectively. Overall, 86.3% of patients experienced treatment-emergent adverse events, the most common being nasopharyngitis, influenza, and back pain. No deaths or new safety signals were reported.

Study details: Findings are 2-year follow-up results of the phase 3b LIBERTY study including 240 patients with episodic migraine who failed 2-4 prior prophylactic treatments, completed placebo-controlled double-blind treatment phase, and were enrolled in the 3-year open-label extension phase with 140 mg erenumab monthly.

Disclosures: This study was supported by Novartis Pharma, Switzerland. Some investigators reported receiving grants and fees from, owning stocks in, or being an employee of various pharmaceutical companies, including Novartis.

Source: Ferrari MD et al. J Neurol Neurosurg Psychiatry. 2021 (Nov 29). Doi: 10.1136/jnnp-2021-327480.

During my usual 2 weeks off over the holidays I did my usual stuff – taxes, read journals, do CME, review legal cases that have come in, hang out with my family, nap with my dogs.

Somewhere in that stretch of time off. I run out of things to do, and that’s when I have to confront an odd truth: I’ve forgotten how to relax.

In medical school and residency I certainly could enjoy the rare weekend time off. I’d watch sports, go running, do things with friends.

But now it’s a different world. My friends, while still people I enjoy, are on the other end of a computer, far away. My interest in sports and movies waned years ago, and I avoid televisions as part of my aversion to the news. Even the books I used to enjoy, such as the late Clive Cussler’s, don’t hold my attention anymore. If I’m going to read anything it’s going to be humor, because the medical field is serious enough as it is.

The bottom line is that it’s hard for me to relax and “do nothing” anymore. I don’t know if that’s just me, or if it’s part of the personality of being a doctor, or both.

If I’m not at my desk working, I feel like I’m not doing anything. Do other doctors feel that way? Have I become a workaholic in my middle age?

Is this a bad thing?

It probably is, and I should look to the beginning of a new year to make some changes. Maybe I should go back to running (or, at this point in my life, walking) or finding some humor books I enjoy and reading them. The old standby of going on a vacation is kind of limited right now.

I’ve been an attending physician for 24 years now, which is still hard to believe. My retirement isn’t (hopefully) anytime soon, but is coming up faster than it seems. If I don’t relearn to relax by then, when will I?
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

During my usual 2 weeks off over the holidays I did my usual stuff – taxes, read journals, do CME, review legal cases that have come in, hang out with my family, nap with my dogs.

Somewhere in that stretch of time off. I run out of things to do, and that’s when I have to confront an odd truth: I’ve forgotten how to relax.

In medical school and residency I certainly could enjoy the rare weekend time off. I’d watch sports, go running, do things with friends.

But now it’s a different world. My friends, while still people I enjoy, are on the other end of a computer, far away. My interest in sports and movies waned years ago, and I avoid televisions as part of my aversion to the news. Even the books I used to enjoy, such as the late Clive Cussler’s, don’t hold my attention anymore. If I’m going to read anything it’s going to be humor, because the medical field is serious enough as it is.

The bottom line is that it’s hard for me to relax and “do nothing” anymore. I don’t know if that’s just me, or if it’s part of the personality of being a doctor, or both.

If I’m not at my desk working, I feel like I’m not doing anything. Do other doctors feel that way? Have I become a workaholic in my middle age?

Is this a bad thing?

It probably is, and I should look to the beginning of a new year to make some changes. Maybe I should go back to running (or, at this point in my life, walking) or finding some humor books I enjoy and reading them. The old standby of going on a vacation is kind of limited right now.

I’ve been an attending physician for 24 years now, which is still hard to believe. My retirement isn’t (hopefully) anytime soon, but is coming up faster than it seems. If I don’t relearn to relax by then, when will I?
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

During my usual 2 weeks off over the holidays I did my usual stuff – taxes, read journals, do CME, review legal cases that have come in, hang out with my family, nap with my dogs.

Somewhere in that stretch of time off. I run out of things to do, and that’s when I have to confront an odd truth: I’ve forgotten how to relax.

In medical school and residency I certainly could enjoy the rare weekend time off. I’d watch sports, go running, do things with friends.

But now it’s a different world. My friends, while still people I enjoy, are on the other end of a computer, far away. My interest in sports and movies waned years ago, and I avoid televisions as part of my aversion to the news. Even the books I used to enjoy, such as the late Clive Cussler’s, don’t hold my attention anymore. If I’m going to read anything it’s going to be humor, because the medical field is serious enough as it is.

The bottom line is that it’s hard for me to relax and “do nothing” anymore. I don’t know if that’s just me, or if it’s part of the personality of being a doctor, or both.

If I’m not at my desk working, I feel like I’m not doing anything. Do other doctors feel that way? Have I become a workaholic in my middle age?

Is this a bad thing?

It probably is, and I should look to the beginning of a new year to make some changes. Maybe I should go back to running (or, at this point in my life, walking) or finding some humor books I enjoy and reading them. The old standby of going on a vacation is kind of limited right now.

I’ve been an attending physician for 24 years now, which is still hard to believe. My retirement isn’t (hopefully) anytime soon, but is coming up faster than it seems. If I don’t relearn to relax by then, when will I?
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Mrs. S.’s long-term chronic obstructive pulmonary disease (COPD) prognosis was grim, and she faced a harder time getting through each day. But neither she nor her primary care physician was willing to embrace strategies other than drugs.

“She felt guilty for continuing to smoke, but also expressed a need to smoke to help her deal with her husband’s cancer and eventual death,” recalled Georgia Narsavage, PhD, RN, ANP-BC, professor emerita of nursing at West Virginia University. “Her primary care physician was reluctant to introduce any treatment other than medications because her family was resistant to facing ‘mother dying.’ ”

SDI Productions/E+

But things changed when Mrs. S. was referred to a palliative-care clinical nurse specialist following a hospitalization. “The goal of palliative care is to support quality of life by relieving symptoms and decreasing suffering. She was assisted to improve functioning overall, and home support services were provided,” Dr. Narsavage said. “They allowed her to live at home relatively pain free with decreased dyspnea for 3 more years until her transition to hospice care a few months before death.

It wasn’t quite a happy ending. But it was a happier ending, and one that palliative care (PC) advocates hope will become more common in pulmonary care. They’re working to convince colleagues that PC is neither another word for hospice nor a sign that anyone is giving up on a patient.
 

Underutilized but beneficial

“Palliative care is underutilized in patients with chronic pulmonary disease, and it’s a missed opportunity to potentially alleviate symptoms and improve quality of life,” said Hilary DuBrock, MD, an internist and critical care pulmonologist with the Mayo Clinic in Rochester, Minn. “Chest physicians should know that it’s important to recognize your limitations in addressing all aspects of a chronic disease, and it’s OK to ask for help from a specialty multidisciplinary team of palliative care providers.”

Statistics back up Dr. DuBrock’s perspective about how PC isn’t common in pulmonary care. A 2017 study examined 181,689 U.S. adult patients who had COPD, received oxygen at home, and were hospitalized for exacerbations from 2006-2012. Just 1.7% received PC, although the number grew over the study period.

Another study published in 2017 examined 3,166 patients over the same period with end-stage idiopathic pulmonary fibrosis (IPF) who were on ventilators. The use of PC is group rose from 2.3% in 2006 to 21.6% in 2012.

More recently, a 2020 meta-analysis examined 19 studies and found that patients with lung cancer were much more likely to receive PC than were those with COPD (odds ratio (OR) = 9.59, P < .001, for hospital-based PC and OR = 8.79, P < .001, for home-based PC).

Patients with lung cancer vs. COPD were also less likely to receive invasive ventilation (OR = .26, P < .001), noninvasive ventilation (OR = .63, P = .009) or CPR (OR = .29, P < .001) or die at a nursing home/long-term care facility (OR = .32, P < .001).

Other studies support PC in COPD: Research in Europe has linked PC in COPD to fewer in-hospital deaths and lower end-of-life expenses. A Canadian study also linked PC to fewer in-hospital deaths in COPD.

Dr. DuBrock said she believes there are a couple reasons why PC isn’t more widely accepted in pulmonology. “There has been little evidence in chronic pulmonary disease regarding the role of PC, and there is a lack of standardized guidelines to help clinicians determine appropriate timing and patient selection for referral,” she said. “There is also a reluctance to refer patients to palliative care since some may think that referral implies that they are giving up on their patients.”

In fact, she said, “if appropriately explained and discussed with patients, PC does not necessarily need to imply to patients that you are giving up on them, but rather that you care enough about them to try to find novel ways to improve their quality of life and relieve their symptoms. Additionally, palliative care can be provided alongside ongoing medical care and treatment of their chronic lung disease.”
 

More than standard care

Another obstacle comes from pulmonologists who claim PC isn’t necessary because they’re handling patient care themselves, said University of Alabama at Birmingham critical care pulmonologist Anand S. Iyer, MD. “They’ll say: ‘I do palliative care, I palliate their breathing. I treat breathlessness and cough, that’s what I do.’ ”

But these symptoms only brush the surface of patient needs, he said. “I don’t think that the average pulmonologist goes beyond that to comprehensive symptom assessment and management of a whole host of symptoms beyond those limited to the lungs – depression, anxiety, fatigue, malnutrition.”

On that latter front, he said, pulmonologists “are really good at having end-of-life conversations at the end of life. We do that every day in the ICU.” Advocates for PC, he said, “want to push that to the clinic a year or two earlier.”
 

Timing and use of PC

When should pulmonologists call in a PC team? Specialists recommend early consultations, even right after a pulmonary disease is diagnosed. “When a pulmonologist diagnoses a condition as a serious illness – especially chronic pulmonary disease – a consultation with a palliative care physician or advanced practice registered nurse” can help assess the need for care and the best time to introduce palliative care to the patient and family “to provide relief and enhance quality of life,” West Virginia University’s Dr. Narsavage said. “Initial diagnosis is not too early to think about the trajectory.

Dr. Iyer agreed that early PC consultation is key. “We’re talking about comprehensive support for the physical, emotional, and spiritual needs of patients and their families. It can grow as needs of patients become more severe.”

For her part, Dr. DuBrock urged colleagues to focus on patient experiences. “The exact timing of when to refer patients with pulmonary disease is not well established,” she said. “Thus, it’s important to take cues from our patients. If they are experiencing significant symptom burden or impaired quality of life or having difficulty coping with their lung disease, then it may be helpful to call in palliative care to address these issues alongside education and discussion with the patient about the role of palliative care to address their unmet needs.”

As an example, Dr. DuBrock spoke of one of her own patients who has pulmonary hypertension (PH), connective tissue disease, and interstitial lung disease. “Her hypertension was relatively well controlled, but she was still quite symptomatic as well as depressed and having difficulty sleeping. I struggled with wanting to help her feel better but I also recognized that more PH therapy wasn’t necessarily the answer,” Dr. Dubrock said. “After some discussions, I referred her to palliative care, and they were extremely helpful with addressing her symptoms with a combination of pharmacologic and nonpharmacologic therapy and also addressing some of her underlying concerns and fears regarding her prognosis and issues related to advance-care planning. Social work was also helpful with addressing some of her financial concerns. I continue to see her on regular basis and treat her PH, but her overall quality of life, sleep, and mood have improved substantially.”
 

First steps

According to specialists, the first step in the PC process with patients is to make sure they understand their conditions, their prognoses, and the role of palliative care itself.

Kathleen Oare Lindell, PhD, RN, associate professor of nursing at Medical University of South Carolina, Charleston, who specializes in PC in pulmonary disease, remembers taking the histories of patients with grim prognoses and “their look on their face was like, ‘I just have a common cold.’ ” In other cases, she said, patients may fear they’ll die immediately when they have 3-5 years to live.

Dr. Lindell, who has worked at a specialty center for patients with interstitial lung disease (ILD), emphasized the importance of speaking in layperson terms that patients understand, such as referring to idiopathic pulmonary fibrosis as “unknown lung scarring.” She also said it’s crucial to be up front about their prognoses.

As for patient understanding of PC, she said, “people think it’s hospice that they’re giving. Palliative care is neither. Instead, it helps to address symptom management, I always tell patients, ‘You’ll be scared, you’ll have a cough. There are medicines and nonpharmacological therapies [that can help], and that’s what palliative care does.’ ”

Keith Swetz, MD, an internist and palliative care specialist at the University of Alabama at Birmingham, agreed that a concise discussion of prognosis is vital. “What do they know about their illness, and what do they understand about what will happen when things get worse?” he said.

“With pulmonary disease, they may be looking at months to years punctuated with a lot of ICU admissions, trips to the hospital, symptom burden, and decline in function. Some will want aggressive treatment and say they’re fine being in the hospital, while others will say being comfortable at home is more important.”

Dr. Swetz’s patients commonly have COPD, interstitial lung disease, pulmonary fibrosis, or PH, and some may have concurrent heart failure. While their prognoses may be poor, he said, discussion about their wishes probably aren’t happening outside of the PC setting.

Or if they are happening, he said, they’re lower quality, boiling down complicated care questions to “Do you want us to do everything yes, or no?

“A lot of it has to do with time,” he said. “Clinicians are busy, they might have a full ICU or pulmonary clinic with 15 minutes to see patients. Sitting down and talking about these things isn’t something that’s prioritized or fits into the work stream very well, and often it hasn’t been reimbursed.”

There typically aren’t insurance hassles regarding referrals for PC, Dr. Iyer said, although finding available specialists may be challenging. A 2019 study projected a wave of retirements of older PC physicians over the next few years, and the ratio of patients to PC specialists may not return to 2019 levels for decades. Rural areas are especially shorthanded. But telehealth may improve access, Dr. Iyer said.

What’s next? Specialists are trying to pin down guidelines for when PC consultation is appropriate in pulmonary disease.
 

Triggers to PC

Dr. Iyer, Dr. Lindell and others authored a 2021 report in the journal CHEST that offers guidance about triggers for PC consultation. The authors cited four “levers” or triggers that are important: worsening lung function, severe symptoms or high burden of care needs, poor prognosis, and frequent severe exacerbations.

“The overall point here is that integrating palliative care into COPD practice isn’t an on-off switch; rather, it should be based upon multiple factors and can evolve over time,” they wrote.

They noted that, “patients with COPD accept palliative care as early as moderate COPD (FEV₁ < 80%), so patients may be ready sooner than clinicians think.”

They added that, “if prognosis is such a concern that a clinician is considering referral for lung transplant evaluation, then concurrent referral to specialist palliative care should be routine practice.

Finally, frequent severe exacerbations, i.e. those that require hospitalization or an emergency room visit, carry a high risk for posthospitalization mortality and are ideal inflection points in the illness trajectory of COPD.”

In the big picture, the authors contend, “palliative care should be integrated early and concurrently with COPD-directed therapies, and its intensity should increase over time as symptoms, needs, and exacerbations worsen approaching EOL [end of life].”

None of the interviewees or other authors reported having any relevant conflicts for this story.

Mrs. S.’s long-term chronic obstructive pulmonary disease (COPD) prognosis was grim, and she faced a harder time getting through each day. But neither she nor her primary care physician was willing to embrace strategies other than drugs.

“She felt guilty for continuing to smoke, but also expressed a need to smoke to help her deal with her husband’s cancer and eventual death,” recalled Georgia Narsavage, PhD, RN, ANP-BC, professor emerita of nursing at West Virginia University. “Her primary care physician was reluctant to introduce any treatment other than medications because her family was resistant to facing ‘mother dying.’ ”

SDI Productions/E+

But things changed when Mrs. S. was referred to a palliative-care clinical nurse specialist following a hospitalization. “The goal of palliative care is to support quality of life by relieving symptoms and decreasing suffering. She was assisted to improve functioning overall, and home support services were provided,” Dr. Narsavage said. “They allowed her to live at home relatively pain free with decreased dyspnea for 3 more years until her transition to hospice care a few months before death.

It wasn’t quite a happy ending. But it was a happier ending, and one that palliative care (PC) advocates hope will become more common in pulmonary care. They’re working to convince colleagues that PC is neither another word for hospice nor a sign that anyone is giving up on a patient.
 

Underutilized but beneficial

“Palliative care is underutilized in patients with chronic pulmonary disease, and it’s a missed opportunity to potentially alleviate symptoms and improve quality of life,” said Hilary DuBrock, MD, an internist and critical care pulmonologist with the Mayo Clinic in Rochester, Minn. “Chest physicians should know that it’s important to recognize your limitations in addressing all aspects of a chronic disease, and it’s OK to ask for help from a specialty multidisciplinary team of palliative care providers.”

Statistics back up Dr. DuBrock’s perspective about how PC isn’t common in pulmonary care. A 2017 study examined 181,689 U.S. adult patients who had COPD, received oxygen at home, and were hospitalized for exacerbations from 2006-2012. Just 1.7% received PC, although the number grew over the study period.

Another study published in 2017 examined 3,166 patients over the same period with end-stage idiopathic pulmonary fibrosis (IPF) who were on ventilators. The use of PC is group rose from 2.3% in 2006 to 21.6% in 2012.

More recently, a 2020 meta-analysis examined 19 studies and found that patients with lung cancer were much more likely to receive PC than were those with COPD (odds ratio (OR) = 9.59, P < .001, for hospital-based PC and OR = 8.79, P < .001, for home-based PC).

Patients with lung cancer vs. COPD were also less likely to receive invasive ventilation (OR = .26, P < .001), noninvasive ventilation (OR = .63, P = .009) or CPR (OR = .29, P < .001) or die at a nursing home/long-term care facility (OR = .32, P < .001).

Other studies support PC in COPD: Research in Europe has linked PC in COPD to fewer in-hospital deaths and lower end-of-life expenses. A Canadian study also linked PC to fewer in-hospital deaths in COPD.

Dr. DuBrock said she believes there are a couple reasons why PC isn’t more widely accepted in pulmonology. “There has been little evidence in chronic pulmonary disease regarding the role of PC, and there is a lack of standardized guidelines to help clinicians determine appropriate timing and patient selection for referral,” she said. “There is also a reluctance to refer patients to palliative care since some may think that referral implies that they are giving up on their patients.”

In fact, she said, “if appropriately explained and discussed with patients, PC does not necessarily need to imply to patients that you are giving up on them, but rather that you care enough about them to try to find novel ways to improve their quality of life and relieve their symptoms. Additionally, palliative care can be provided alongside ongoing medical care and treatment of their chronic lung disease.”
 

More than standard care

Another obstacle comes from pulmonologists who claim PC isn’t necessary because they’re handling patient care themselves, said University of Alabama at Birmingham critical care pulmonologist Anand S. Iyer, MD. “They’ll say: ‘I do palliative care, I palliate their breathing. I treat breathlessness and cough, that’s what I do.’ ”

But these symptoms only brush the surface of patient needs, he said. “I don’t think that the average pulmonologist goes beyond that to comprehensive symptom assessment and management of a whole host of symptoms beyond those limited to the lungs – depression, anxiety, fatigue, malnutrition.”

On that latter front, he said, pulmonologists “are really good at having end-of-life conversations at the end of life. We do that every day in the ICU.” Advocates for PC, he said, “want to push that to the clinic a year or two earlier.”
 

Timing and use of PC

When should pulmonologists call in a PC team? Specialists recommend early consultations, even right after a pulmonary disease is diagnosed. “When a pulmonologist diagnoses a condition as a serious illness – especially chronic pulmonary disease – a consultation with a palliative care physician or advanced practice registered nurse” can help assess the need for care and the best time to introduce palliative care to the patient and family “to provide relief and enhance quality of life,” West Virginia University’s Dr. Narsavage said. “Initial diagnosis is not too early to think about the trajectory.

Dr. Iyer agreed that early PC consultation is key. “We’re talking about comprehensive support for the physical, emotional, and spiritual needs of patients and their families. It can grow as needs of patients become more severe.”

For her part, Dr. DuBrock urged colleagues to focus on patient experiences. “The exact timing of when to refer patients with pulmonary disease is not well established,” she said. “Thus, it’s important to take cues from our patients. If they are experiencing significant symptom burden or impaired quality of life or having difficulty coping with their lung disease, then it may be helpful to call in palliative care to address these issues alongside education and discussion with the patient about the role of palliative care to address their unmet needs.”

As an example, Dr. DuBrock spoke of one of her own patients who has pulmonary hypertension (PH), connective tissue disease, and interstitial lung disease. “Her hypertension was relatively well controlled, but she was still quite symptomatic as well as depressed and having difficulty sleeping. I struggled with wanting to help her feel better but I also recognized that more PH therapy wasn’t necessarily the answer,” Dr. Dubrock said. “After some discussions, I referred her to palliative care, and they were extremely helpful with addressing her symptoms with a combination of pharmacologic and nonpharmacologic therapy and also addressing some of her underlying concerns and fears regarding her prognosis and issues related to advance-care planning. Social work was also helpful with addressing some of her financial concerns. I continue to see her on regular basis and treat her PH, but her overall quality of life, sleep, and mood have improved substantially.”
 

First steps

According to specialists, the first step in the PC process with patients is to make sure they understand their conditions, their prognoses, and the role of palliative care itself.

Kathleen Oare Lindell, PhD, RN, associate professor of nursing at Medical University of South Carolina, Charleston, who specializes in PC in pulmonary disease, remembers taking the histories of patients with grim prognoses and “their look on their face was like, ‘I just have a common cold.’ ” In other cases, she said, patients may fear they’ll die immediately when they have 3-5 years to live.

Dr. Lindell, who has worked at a specialty center for patients with interstitial lung disease (ILD), emphasized the importance of speaking in layperson terms that patients understand, such as referring to idiopathic pulmonary fibrosis as “unknown lung scarring.” She also said it’s crucial to be up front about their prognoses.

As for patient understanding of PC, she said, “people think it’s hospice that they’re giving. Palliative care is neither. Instead, it helps to address symptom management, I always tell patients, ‘You’ll be scared, you’ll have a cough. There are medicines and nonpharmacological therapies [that can help], and that’s what palliative care does.’ ”

Keith Swetz, MD, an internist and palliative care specialist at the University of Alabama at Birmingham, agreed that a concise discussion of prognosis is vital. “What do they know about their illness, and what do they understand about what will happen when things get worse?” he said.

“With pulmonary disease, they may be looking at months to years punctuated with a lot of ICU admissions, trips to the hospital, symptom burden, and decline in function. Some will want aggressive treatment and say they’re fine being in the hospital, while others will say being comfortable at home is more important.”

Dr. Swetz’s patients commonly have COPD, interstitial lung disease, pulmonary fibrosis, or PH, and some may have concurrent heart failure. While their prognoses may be poor, he said, discussion about their wishes probably aren’t happening outside of the PC setting.

Or if they are happening, he said, they’re lower quality, boiling down complicated care questions to “Do you want us to do everything yes, or no?

“A lot of it has to do with time,” he said. “Clinicians are busy, they might have a full ICU or pulmonary clinic with 15 minutes to see patients. Sitting down and talking about these things isn’t something that’s prioritized or fits into the work stream very well, and often it hasn’t been reimbursed.”

There typically aren’t insurance hassles regarding referrals for PC, Dr. Iyer said, although finding available specialists may be challenging. A 2019 study projected a wave of retirements of older PC physicians over the next few years, and the ratio of patients to PC specialists may not return to 2019 levels for decades. Rural areas are especially shorthanded. But telehealth may improve access, Dr. Iyer said.

What’s next? Specialists are trying to pin down guidelines for when PC consultation is appropriate in pulmonary disease.
 

Triggers to PC

Dr. Iyer, Dr. Lindell and others authored a 2021 report in the journal CHEST that offers guidance about triggers for PC consultation. The authors cited four “levers” or triggers that are important: worsening lung function, severe symptoms or high burden of care needs, poor prognosis, and frequent severe exacerbations.

“The overall point here is that integrating palliative care into COPD practice isn’t an on-off switch; rather, it should be based upon multiple factors and can evolve over time,” they wrote.

They noted that, “patients with COPD accept palliative care as early as moderate COPD (FEV₁ < 80%), so patients may be ready sooner than clinicians think.”

They added that, “if prognosis is such a concern that a clinician is considering referral for lung transplant evaluation, then concurrent referral to specialist palliative care should be routine practice.

Finally, frequent severe exacerbations, i.e. those that require hospitalization or an emergency room visit, carry a high risk for posthospitalization mortality and are ideal inflection points in the illness trajectory of COPD.”

In the big picture, the authors contend, “palliative care should be integrated early and concurrently with COPD-directed therapies, and its intensity should increase over time as symptoms, needs, and exacerbations worsen approaching EOL [end of life].”

None of the interviewees or other authors reported having any relevant conflicts for this story.

Mrs. S.’s long-term chronic obstructive pulmonary disease (COPD) prognosis was grim, and she faced a harder time getting through each day. But neither she nor her primary care physician was willing to embrace strategies other than drugs.

“She felt guilty for continuing to smoke, but also expressed a need to smoke to help her deal with her husband’s cancer and eventual death,” recalled Georgia Narsavage, PhD, RN, ANP-BC, professor emerita of nursing at West Virginia University. “Her primary care physician was reluctant to introduce any treatment other than medications because her family was resistant to facing ‘mother dying.’ ”

SDI Productions/E+

But things changed when Mrs. S. was referred to a palliative-care clinical nurse specialist following a hospitalization. “The goal of palliative care is to support quality of life by relieving symptoms and decreasing suffering. She was assisted to improve functioning overall, and home support services were provided,” Dr. Narsavage said. “They allowed her to live at home relatively pain free with decreased dyspnea for 3 more years until her transition to hospice care a few months before death.

It wasn’t quite a happy ending. But it was a happier ending, and one that palliative care (PC) advocates hope will become more common in pulmonary care. They’re working to convince colleagues that PC is neither another word for hospice nor a sign that anyone is giving up on a patient.
 

Underutilized but beneficial

“Palliative care is underutilized in patients with chronic pulmonary disease, and it’s a missed opportunity to potentially alleviate symptoms and improve quality of life,” said Hilary DuBrock, MD, an internist and critical care pulmonologist with the Mayo Clinic in Rochester, Minn. “Chest physicians should know that it’s important to recognize your limitations in addressing all aspects of a chronic disease, and it’s OK to ask for help from a specialty multidisciplinary team of palliative care providers.”

Statistics back up Dr. DuBrock’s perspective about how PC isn’t common in pulmonary care. A 2017 study examined 181,689 U.S. adult patients who had COPD, received oxygen at home, and were hospitalized for exacerbations from 2006-2012. Just 1.7% received PC, although the number grew over the study period.

Another study published in 2017 examined 3,166 patients over the same period with end-stage idiopathic pulmonary fibrosis (IPF) who were on ventilators. The use of PC is group rose from 2.3% in 2006 to 21.6% in 2012.

More recently, a 2020 meta-analysis examined 19 studies and found that patients with lung cancer were much more likely to receive PC than were those with COPD (odds ratio (OR) = 9.59, P < .001, for hospital-based PC and OR = 8.79, P < .001, for home-based PC).

Patients with lung cancer vs. COPD were also less likely to receive invasive ventilation (OR = .26, P < .001), noninvasive ventilation (OR = .63, P = .009) or CPR (OR = .29, P < .001) or die at a nursing home/long-term care facility (OR = .32, P < .001).

Other studies support PC in COPD: Research in Europe has linked PC in COPD to fewer in-hospital deaths and lower end-of-life expenses. A Canadian study also linked PC to fewer in-hospital deaths in COPD.

Dr. DuBrock said she believes there are a couple reasons why PC isn’t more widely accepted in pulmonology. “There has been little evidence in chronic pulmonary disease regarding the role of PC, and there is a lack of standardized guidelines to help clinicians determine appropriate timing and patient selection for referral,” she said. “There is also a reluctance to refer patients to palliative care since some may think that referral implies that they are giving up on their patients.”

In fact, she said, “if appropriately explained and discussed with patients, PC does not necessarily need to imply to patients that you are giving up on them, but rather that you care enough about them to try to find novel ways to improve their quality of life and relieve their symptoms. Additionally, palliative care can be provided alongside ongoing medical care and treatment of their chronic lung disease.”
 

More than standard care

Another obstacle comes from pulmonologists who claim PC isn’t necessary because they’re handling patient care themselves, said University of Alabama at Birmingham critical care pulmonologist Anand S. Iyer, MD. “They’ll say: ‘I do palliative care, I palliate their breathing. I treat breathlessness and cough, that’s what I do.’ ”

But these symptoms only brush the surface of patient needs, he said. “I don’t think that the average pulmonologist goes beyond that to comprehensive symptom assessment and management of a whole host of symptoms beyond those limited to the lungs – depression, anxiety, fatigue, malnutrition.”

On that latter front, he said, pulmonologists “are really good at having end-of-life conversations at the end of life. We do that every day in the ICU.” Advocates for PC, he said, “want to push that to the clinic a year or two earlier.”
 

Timing and use of PC

When should pulmonologists call in a PC team? Specialists recommend early consultations, even right after a pulmonary disease is diagnosed. “When a pulmonologist diagnoses a condition as a serious illness – especially chronic pulmonary disease – a consultation with a palliative care physician or advanced practice registered nurse” can help assess the need for care and the best time to introduce palliative care to the patient and family “to provide relief and enhance quality of life,” West Virginia University’s Dr. Narsavage said. “Initial diagnosis is not too early to think about the trajectory.

Dr. Iyer agreed that early PC consultation is key. “We’re talking about comprehensive support for the physical, emotional, and spiritual needs of patients and their families. It can grow as needs of patients become more severe.”

For her part, Dr. DuBrock urged colleagues to focus on patient experiences. “The exact timing of when to refer patients with pulmonary disease is not well established,” she said. “Thus, it’s important to take cues from our patients. If they are experiencing significant symptom burden or impaired quality of life or having difficulty coping with their lung disease, then it may be helpful to call in palliative care to address these issues alongside education and discussion with the patient about the role of palliative care to address their unmet needs.”

As an example, Dr. DuBrock spoke of one of her own patients who has pulmonary hypertension (PH), connective tissue disease, and interstitial lung disease. “Her hypertension was relatively well controlled, but she was still quite symptomatic as well as depressed and having difficulty sleeping. I struggled with wanting to help her feel better but I also recognized that more PH therapy wasn’t necessarily the answer,” Dr. Dubrock said. “After some discussions, I referred her to palliative care, and they were extremely helpful with addressing her symptoms with a combination of pharmacologic and nonpharmacologic therapy and also addressing some of her underlying concerns and fears regarding her prognosis and issues related to advance-care planning. Social work was also helpful with addressing some of her financial concerns. I continue to see her on regular basis and treat her PH, but her overall quality of life, sleep, and mood have improved substantially.”
 

First steps

According to specialists, the first step in the PC process with patients is to make sure they understand their conditions, their prognoses, and the role of palliative care itself.

Kathleen Oare Lindell, PhD, RN, associate professor of nursing at Medical University of South Carolina, Charleston, who specializes in PC in pulmonary disease, remembers taking the histories of patients with grim prognoses and “their look on their face was like, ‘I just have a common cold.’ ” In other cases, she said, patients may fear they’ll die immediately when they have 3-5 years to live.

Dr. Lindell, who has worked at a specialty center for patients with interstitial lung disease (ILD), emphasized the importance of speaking in layperson terms that patients understand, such as referring to idiopathic pulmonary fibrosis as “unknown lung scarring.” She also said it’s crucial to be up front about their prognoses.

As for patient understanding of PC, she said, “people think it’s hospice that they’re giving. Palliative care is neither. Instead, it helps to address symptom management, I always tell patients, ‘You’ll be scared, you’ll have a cough. There are medicines and nonpharmacological therapies [that can help], and that’s what palliative care does.’ ”

Keith Swetz, MD, an internist and palliative care specialist at the University of Alabama at Birmingham, agreed that a concise discussion of prognosis is vital. “What do they know about their illness, and what do they understand about what will happen when things get worse?” he said.

“With pulmonary disease, they may be looking at months to years punctuated with a lot of ICU admissions, trips to the hospital, symptom burden, and decline in function. Some will want aggressive treatment and say they’re fine being in the hospital, while others will say being comfortable at home is more important.”

Dr. Swetz’s patients commonly have COPD, interstitial lung disease, pulmonary fibrosis, or PH, and some may have concurrent heart failure. While their prognoses may be poor, he said, discussion about their wishes probably aren’t happening outside of the PC setting.

Or if they are happening, he said, they’re lower quality, boiling down complicated care questions to “Do you want us to do everything yes, or no?

“A lot of it has to do with time,” he said. “Clinicians are busy, they might have a full ICU or pulmonary clinic with 15 minutes to see patients. Sitting down and talking about these things isn’t something that’s prioritized or fits into the work stream very well, and often it hasn’t been reimbursed.”

There typically aren’t insurance hassles regarding referrals for PC, Dr. Iyer said, although finding available specialists may be challenging. A 2019 study projected a wave of retirements of older PC physicians over the next few years, and the ratio of patients to PC specialists may not return to 2019 levels for decades. Rural areas are especially shorthanded. But telehealth may improve access, Dr. Iyer said.

What’s next? Specialists are trying to pin down guidelines for when PC consultation is appropriate in pulmonary disease.
 

Triggers to PC

Dr. Iyer, Dr. Lindell and others authored a 2021 report in the journal CHEST that offers guidance about triggers for PC consultation. The authors cited four “levers” or triggers that are important: worsening lung function, severe symptoms or high burden of care needs, poor prognosis, and frequent severe exacerbations.

“The overall point here is that integrating palliative care into COPD practice isn’t an on-off switch; rather, it should be based upon multiple factors and can evolve over time,” they wrote.

They noted that, “patients with COPD accept palliative care as early as moderate COPD (FEV₁ < 80%), so patients may be ready sooner than clinicians think.”

They added that, “if prognosis is such a concern that a clinician is considering referral for lung transplant evaluation, then concurrent referral to specialist palliative care should be routine practice.

Finally, frequent severe exacerbations, i.e. those that require hospitalization or an emergency room visit, carry a high risk for posthospitalization mortality and are ideal inflection points in the illness trajectory of COPD.”

In the big picture, the authors contend, “palliative care should be integrated early and concurrently with COPD-directed therapies, and its intensity should increase over time as symptoms, needs, and exacerbations worsen approaching EOL [end of life].”

None of the interviewees or other authors reported having any relevant conflicts for this story.

A new study has found that proactive therapeutic drug monitoring (TDM) with maintenance infliximab is more effective than standard therapy in sustaining control of immune-mediated inflammatory diseases.

The findings from the Norwegian Drug Monitoring B (NOR-DRUM B) trial, published Dec. 21, 2021, in JAMA, provide greater support to the usefulness of TDM in proactively monitoring serum drug levels and antidrug antibodies to infliximab, which has been previously shown to have benefit in patients with inflammatory bowel disease, but leave the benefits of proactive versus reactive monitoring and the cost-effectiveness of the approach in individual immune-mediated inflammatory diseases still open to questioning.

Alexander Raths/ThinkStock

TDM is ‘not the holy grail,’ and that’s OK

“This is an important milestone in the field of TDM with biologics for immunoinflammatory diseases,” Niels Vande Casteele, PharmD, PhD, of the University of California, San Diego, told this news organization. He was not involved in the study.

“When you read through the study, you can see the authors used the TAXIT trial results to inform their study design and the sample size,” he added, referencing his 2015 study on infliximab guide dosing for patients with inflammatory bowel disease, “the first-ever randomized, controlled trial of proactive TDM with any biologic.”

For the TAXIT study’s primary outcome of clinical and biochemical remission at 1 year, “continued concentration-based dosing was not superior to clinically based dosing for achieving remission.” But in regard to their secondary outcome of sustained remission, their results were quite similar to the results of NOR-DRUM B.

“If anything, we already showed a benefit of proactive TDM in 2015,” he said, “but I’m very glad that the authors looked at the trial design and teased out where TDM could be the most important and have the biggest impact, which is to maintain that sustained disease remission over a prolonged period.”

As for next steps, Dr. Vande Casteele noted that TDM isn’t a one-size-fits-all upgrade for drug treatments. But that doesn’t mean it won’t be very useful in many patients.

“What the paper is saying, and what we’ve been finding all along, is that TDM is not the holy grail,” he said. “But it is a tool in the physicians’ toolbox to optimize treatments and maximize efficacy, and there are some patients who truly benefit from it.”
 

Study details

To determine if proactive TDM with infliximab led to more sustained disease control than standard therapy, first author Silje Watterdal Syversen, MD, PhD, of Diakonhjemmet Hospital in Oslo, and coauthors conducted a 52-week, randomized, parallel-group, open-label trial. From 20 Norwegian hospitals, they recruited 458 patients with rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn’s disease (n = 68), or psoriasis (n = 37) who were undergoing maintenance therapy with the biologic.

The 454 patients who received at least one randomly allocated dose of infliximab were treated with one of two strategies: TDM (n = 227) or standard therapy (n = 227). The TDM group received dose and interval adjustments based on an algorithm that factored in serum drug levels and antidrug antibodies. The standard therapy group was treated on the basis of clinical judgment and physician discretion. The average age across groups was roughly 45 years, and just under 50% were women.

Overall, sustained disease control without worsening was achieved in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group, with an estimated adjusted difference of 17.6% (95% confidence interval, 9.0%-26.2%; P < .001). The estimated hazard ratio of disease worsening was 2.1 (95% CI, 1.5-2.9) for standard therapy, compared with TDM. A total of 27 patients (15%) in the standard therapy group and 21 patients (9.2%) in the TDM group developed significant levels of antidrug antibodies, defined here as 50 mcg/L or more.

A total of 34 patients discontinued infliximab in each group; in the TDM group, most discontinued because of antidrug antibody formation, while the main reason for discontinuing in the standard therapy group was disease worsening. Adverse events were reported in 137 patients (60%) in the TDM group and 142 patients (63%) in the standard therapy group.

Removing barriers to TDM

It’s not clear that proactive TDM will benefit treatment with all biologic disease-modifying antirheumatic drugs (bDMARDs), but the findings from Dr. Syversen and colleagues state the clear value of using drug monitoring to guide maintenance therapy with infliximab, Zachary S. Wallace, MD, and Jeffrey A. Sparks, MD, wrote in an accompanying editorial.

“The relatively large sample size and rigorous study design ... helped to overcome some limitations of previous observational studies and small clinical trials that yielded conflicting results regarding TDM,” they added, noting that these findings contrasted somewhat with the NOR-DRUM A trial in which TDM did not improve remission induction in patients initiating infliximab therapy.

Along those lines, they recognized that TDM appears to have a greater effect in patients on maintenance infliximab, compared with those just starting the drug, surmising – among several explanations – that achieving remission in someone beginning treatment is a more difficult outcome to achieve than controlling disease in a patient already in remission.

For now, more clinical trials assessing specific diseases and involving other bDMARDs are needed; Dr. Wallace and Dr. Sparks stated that it’s time to remove barriers to implementing TDM – including the need for medical insurance preauthorization before increasing drug doses – and potentially “introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases.”

The authors acknowledged their study’s limitations, including disease worsening being measured in part by patient-physician consensus and thus potentially subject to bias. In addition, they did not have the statistical ability to test TDM effectiveness in each of the six disease groups, noting that “these diseases have inherent differences, and findings may not be completely generalizable across groups.”

The study was funded by grants from the Norwegian Regional Health Authorities and the South-Eastern Norway Regional Health Authorities. The authors reported numerous potential conflicts of interest, including receiving personal fees and grants from various pharmaceutical companies. Dr. Wallace and Dr. Sparks also reported receiving research support and fees from pharmaceutical companies. Dr. Vande Casteele reported receiving research grants and personal fees from multiple pharmaceutical companies, all outside of the reviewed work.

A version of this article first appeared on Medscape.com.

A new study has found that proactive therapeutic drug monitoring (TDM) with maintenance infliximab is more effective than standard therapy in sustaining control of immune-mediated inflammatory diseases.

The findings from the Norwegian Drug Monitoring B (NOR-DRUM B) trial, published Dec. 21, 2021, in JAMA, provide greater support to the usefulness of TDM in proactively monitoring serum drug levels and antidrug antibodies to infliximab, which has been previously shown to have benefit in patients with inflammatory bowel disease, but leave the benefits of proactive versus reactive monitoring and the cost-effectiveness of the approach in individual immune-mediated inflammatory diseases still open to questioning.

Alexander Raths/ThinkStock

TDM is ‘not the holy grail,’ and that’s OK

“This is an important milestone in the field of TDM with biologics for immunoinflammatory diseases,” Niels Vande Casteele, PharmD, PhD, of the University of California, San Diego, told this news organization. He was not involved in the study.

“When you read through the study, you can see the authors used the TAXIT trial results to inform their study design and the sample size,” he added, referencing his 2015 study on infliximab guide dosing for patients with inflammatory bowel disease, “the first-ever randomized, controlled trial of proactive TDM with any biologic.”

For the TAXIT study’s primary outcome of clinical and biochemical remission at 1 year, “continued concentration-based dosing was not superior to clinically based dosing for achieving remission.” But in regard to their secondary outcome of sustained remission, their results were quite similar to the results of NOR-DRUM B.

“If anything, we already showed a benefit of proactive TDM in 2015,” he said, “but I’m very glad that the authors looked at the trial design and teased out where TDM could be the most important and have the biggest impact, which is to maintain that sustained disease remission over a prolonged period.”

As for next steps, Dr. Vande Casteele noted that TDM isn’t a one-size-fits-all upgrade for drug treatments. But that doesn’t mean it won’t be very useful in many patients.

“What the paper is saying, and what we’ve been finding all along, is that TDM is not the holy grail,” he said. “But it is a tool in the physicians’ toolbox to optimize treatments and maximize efficacy, and there are some patients who truly benefit from it.”
 

Study details

To determine if proactive TDM with infliximab led to more sustained disease control than standard therapy, first author Silje Watterdal Syversen, MD, PhD, of Diakonhjemmet Hospital in Oslo, and coauthors conducted a 52-week, randomized, parallel-group, open-label trial. From 20 Norwegian hospitals, they recruited 458 patients with rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn’s disease (n = 68), or psoriasis (n = 37) who were undergoing maintenance therapy with the biologic.

The 454 patients who received at least one randomly allocated dose of infliximab were treated with one of two strategies: TDM (n = 227) or standard therapy (n = 227). The TDM group received dose and interval adjustments based on an algorithm that factored in serum drug levels and antidrug antibodies. The standard therapy group was treated on the basis of clinical judgment and physician discretion. The average age across groups was roughly 45 years, and just under 50% were women.

Overall, sustained disease control without worsening was achieved in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group, with an estimated adjusted difference of 17.6% (95% confidence interval, 9.0%-26.2%; P < .001). The estimated hazard ratio of disease worsening was 2.1 (95% CI, 1.5-2.9) for standard therapy, compared with TDM. A total of 27 patients (15%) in the standard therapy group and 21 patients (9.2%) in the TDM group developed significant levels of antidrug antibodies, defined here as 50 mcg/L or more.

A total of 34 patients discontinued infliximab in each group; in the TDM group, most discontinued because of antidrug antibody formation, while the main reason for discontinuing in the standard therapy group was disease worsening. Adverse events were reported in 137 patients (60%) in the TDM group and 142 patients (63%) in the standard therapy group.

Removing barriers to TDM

It’s not clear that proactive TDM will benefit treatment with all biologic disease-modifying antirheumatic drugs (bDMARDs), but the findings from Dr. Syversen and colleagues state the clear value of using drug monitoring to guide maintenance therapy with infliximab, Zachary S. Wallace, MD, and Jeffrey A. Sparks, MD, wrote in an accompanying editorial.

“The relatively large sample size and rigorous study design ... helped to overcome some limitations of previous observational studies and small clinical trials that yielded conflicting results regarding TDM,” they added, noting that these findings contrasted somewhat with the NOR-DRUM A trial in which TDM did not improve remission induction in patients initiating infliximab therapy.

Along those lines, they recognized that TDM appears to have a greater effect in patients on maintenance infliximab, compared with those just starting the drug, surmising – among several explanations – that achieving remission in someone beginning treatment is a more difficult outcome to achieve than controlling disease in a patient already in remission.

For now, more clinical trials assessing specific diseases and involving other bDMARDs are needed; Dr. Wallace and Dr. Sparks stated that it’s time to remove barriers to implementing TDM – including the need for medical insurance preauthorization before increasing drug doses – and potentially “introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases.”

The authors acknowledged their study’s limitations, including disease worsening being measured in part by patient-physician consensus and thus potentially subject to bias. In addition, they did not have the statistical ability to test TDM effectiveness in each of the six disease groups, noting that “these diseases have inherent differences, and findings may not be completely generalizable across groups.”

The study was funded by grants from the Norwegian Regional Health Authorities and the South-Eastern Norway Regional Health Authorities. The authors reported numerous potential conflicts of interest, including receiving personal fees and grants from various pharmaceutical companies. Dr. Wallace and Dr. Sparks also reported receiving research support and fees from pharmaceutical companies. Dr. Vande Casteele reported receiving research grants and personal fees from multiple pharmaceutical companies, all outside of the reviewed work.

A version of this article first appeared on Medscape.com.

A new study has found that proactive therapeutic drug monitoring (TDM) with maintenance infliximab is more effective than standard therapy in sustaining control of immune-mediated inflammatory diseases.

The findings from the Norwegian Drug Monitoring B (NOR-DRUM B) trial, published Dec. 21, 2021, in JAMA, provide greater support to the usefulness of TDM in proactively monitoring serum drug levels and antidrug antibodies to infliximab, which has been previously shown to have benefit in patients with inflammatory bowel disease, but leave the benefits of proactive versus reactive monitoring and the cost-effectiveness of the approach in individual immune-mediated inflammatory diseases still open to questioning.

Alexander Raths/ThinkStock

TDM is ‘not the holy grail,’ and that’s OK

“This is an important milestone in the field of TDM with biologics for immunoinflammatory diseases,” Niels Vande Casteele, PharmD, PhD, of the University of California, San Diego, told this news organization. He was not involved in the study.

“When you read through the study, you can see the authors used the TAXIT trial results to inform their study design and the sample size,” he added, referencing his 2015 study on infliximab guide dosing for patients with inflammatory bowel disease, “the first-ever randomized, controlled trial of proactive TDM with any biologic.”

For the TAXIT study’s primary outcome of clinical and biochemical remission at 1 year, “continued concentration-based dosing was not superior to clinically based dosing for achieving remission.” But in regard to their secondary outcome of sustained remission, their results were quite similar to the results of NOR-DRUM B.

“If anything, we already showed a benefit of proactive TDM in 2015,” he said, “but I’m very glad that the authors looked at the trial design and teased out where TDM could be the most important and have the biggest impact, which is to maintain that sustained disease remission over a prolonged period.”

As for next steps, Dr. Vande Casteele noted that TDM isn’t a one-size-fits-all upgrade for drug treatments. But that doesn’t mean it won’t be very useful in many patients.

“What the paper is saying, and what we’ve been finding all along, is that TDM is not the holy grail,” he said. “But it is a tool in the physicians’ toolbox to optimize treatments and maximize efficacy, and there are some patients who truly benefit from it.”
 

Study details

To determine if proactive TDM with infliximab led to more sustained disease control than standard therapy, first author Silje Watterdal Syversen, MD, PhD, of Diakonhjemmet Hospital in Oslo, and coauthors conducted a 52-week, randomized, parallel-group, open-label trial. From 20 Norwegian hospitals, they recruited 458 patients with rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn’s disease (n = 68), or psoriasis (n = 37) who were undergoing maintenance therapy with the biologic.

The 454 patients who received at least one randomly allocated dose of infliximab were treated with one of two strategies: TDM (n = 227) or standard therapy (n = 227). The TDM group received dose and interval adjustments based on an algorithm that factored in serum drug levels and antidrug antibodies. The standard therapy group was treated on the basis of clinical judgment and physician discretion. The average age across groups was roughly 45 years, and just under 50% were women.

Overall, sustained disease control without worsening was achieved in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group, with an estimated adjusted difference of 17.6% (95% confidence interval, 9.0%-26.2%; P < .001). The estimated hazard ratio of disease worsening was 2.1 (95% CI, 1.5-2.9) for standard therapy, compared with TDM. A total of 27 patients (15%) in the standard therapy group and 21 patients (9.2%) in the TDM group developed significant levels of antidrug antibodies, defined here as 50 mcg/L or more.

A total of 34 patients discontinued infliximab in each group; in the TDM group, most discontinued because of antidrug antibody formation, while the main reason for discontinuing in the standard therapy group was disease worsening. Adverse events were reported in 137 patients (60%) in the TDM group and 142 patients (63%) in the standard therapy group.

Removing barriers to TDM

It’s not clear that proactive TDM will benefit treatment with all biologic disease-modifying antirheumatic drugs (bDMARDs), but the findings from Dr. Syversen and colleagues state the clear value of using drug monitoring to guide maintenance therapy with infliximab, Zachary S. Wallace, MD, and Jeffrey A. Sparks, MD, wrote in an accompanying editorial.

“The relatively large sample size and rigorous study design ... helped to overcome some limitations of previous observational studies and small clinical trials that yielded conflicting results regarding TDM,” they added, noting that these findings contrasted somewhat with the NOR-DRUM A trial in which TDM did not improve remission induction in patients initiating infliximab therapy.

Along those lines, they recognized that TDM appears to have a greater effect in patients on maintenance infliximab, compared with those just starting the drug, surmising – among several explanations – that achieving remission in someone beginning treatment is a more difficult outcome to achieve than controlling disease in a patient already in remission.

For now, more clinical trials assessing specific diseases and involving other bDMARDs are needed; Dr. Wallace and Dr. Sparks stated that it’s time to remove barriers to implementing TDM – including the need for medical insurance preauthorization before increasing drug doses – and potentially “introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases.”

The authors acknowledged their study’s limitations, including disease worsening being measured in part by patient-physician consensus and thus potentially subject to bias. In addition, they did not have the statistical ability to test TDM effectiveness in each of the six disease groups, noting that “these diseases have inherent differences, and findings may not be completely generalizable across groups.”

The study was funded by grants from the Norwegian Regional Health Authorities and the South-Eastern Norway Regional Health Authorities. The authors reported numerous potential conflicts of interest, including receiving personal fees and grants from various pharmaceutical companies. Dr. Wallace and Dr. Sparks also reported receiving research support and fees from pharmaceutical companies. Dr. Vande Casteele reported receiving research grants and personal fees from multiple pharmaceutical companies, all outside of the reviewed work.

A version of this article first appeared on Medscape.com.

Inpatient and outpatient treatments of transient ischemic attack (TIA) or minor ischemic stroke (mIS) yield comparable safety outcomes, new research suggests. In a meta-analysis of more than 200,000 patients with TIA or mIS, risk for subsequent stroke within 90 days was 2.1% for those treated in a TIA clinic versus 2.8% for patients treated in inpatient settings, which was not significantly different. The risk for patients treated in an emergency department was higher, at 3.5%.

“The message is that if you do the correct risk stratification and then triage patients based on their risk profile, you can safely discharge and have a timely follow-up for the patients who have low risk for a subsequent event,” said coinvestigator Ramin Zand, MD, vascular neurologist and stroke attending physician at Geisinger Health System, Danville, Pennsylvania.

The findings were published online Jan. 5 in JAMA Network Open.
 

Higher risk in EDs

There is currently no consensus on the care protocol for patients with TIA or mIS, and the rate at which these patients are hospitalized varies by region, hospital, and practitioner, the investigators noted.

Previous studies have indicated that outpatient management of certain individuals with TIA can be safe and cost-effective.

The current researchers searched for retrospective and prospective studies of adult patients that provided information about ischemic stroke after TIA or mIS. Studies that used time- and tissue-based definitions of TIA were included, as well as studies that used various definitions of mIS.

The investigators examined care provided at TIA clinics, inpatient settings (such as medical-surgical units, stroke units, or observation units), EDs, and unspecified settings. Their main aim was to compare outcomes between TIA clinics and inpatient settings.

In all, 226,683 patients (recruited between 1981 and 2018) from 71 studies were included in the meta-analysis. The studies examined 101 cohorts, 24 of which were studied prospectively. Among the 5,636 patients who received care in TIA clinics, the mean age was 65.7 years, and 50.8% of this group were men. Among the 130,139 inpatients, the mean age was 78.3 years, and 61.6% of the group were women.

Results showed no significant difference in risk for subsequent stroke between patients treated in the inpatient and outpatient settings.

Among patients treated in a TIA clinic, risk for subsequent stroke following a TIA or mIS was 0.3% within 2 days, 1.0% within 7 days, 1.3% within 30 days, and 2.1% within 90 days. Among those treated as inpatients, risk for subsequent stroke was 0.5% within 2 days, 1.2% within 7 days, 1.6% within 30 days, and 2.8% within 90 days.

Risk for subsequent stroke was higher among patients treated in the ED and in unspecified settings. At the EDs, the risk was 1.9% within 2 days, 3.4% within 7 days, 3.5% within 30 days, and 3.5% within 90 days. Among those treated in unspecified settings, the risk was 2.2% within 2 days, 3.4% within 7 days, 4.2% within 30 days, and 6.0% within 90 days.

Patients treated in the ED also had a significantly higher risk for subsequent stroke at 2 and 7 days, compared with those treated in inpatient settings and a significantly higher risk for subsequent stroke at 2, 7, and 90 days, compared with those treated in TIA clinics.
 

‘Most comprehensive look’

“This is the most comprehensive look at all the studies to try and answer this research question,” said Dr. Zand. The results were similar to what was expected, he added.

The infrastructure and resources differed among the sites at which the various studies were conducted, and the investigators adjusted for these differences as much as possible, Dr. Zand noted. A certain amount of selection bias may remain, but it does not affect the overall conclusion, he added.

“Timely outpatient care among low-risk TIA patients is both feasible and safe,” he said.

Dr. Zand noted that the findings have implications not only for patient management but also for the management of the health system. “It’s not feasible nor desirable to admit all the TIA patients, especially with the lessons that we learned from COVID, the burden on the health systems, and the fact that many hospitals are operating at full capacity right now,” he said.

The recommendation is to hospitalize high-risk patients and provide outpatient evaluation and workup to low-risk patients, he added. “This is exactly what we saw in this study,” Dr. Zand said.
 

Selection bias?

Commenting on the research, Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, noted that evaluation of patients with TIA or mIS “can be done very well as an outpatient” if clinicians have experienced personnel, the outpatient facilities to do the studies necessary, and criteria in place for deciding who to admit or not admit.

However, the decision on whether to choose an inpatient or outpatient approach for a particular patient is complicated, said Dr. Caplan, who was not involved with the research.

Clinicians must consider factors such as whether the patient is mobile, has a car, or has a significant other. The patient’s symptoms and past illnesses also influence the decision, he added.

Dr. Caplan noted that in the meta-analysis, far fewer patients were seen in the TIA clinics than were seen in the inpatient setting. In addition, none of the studies used uniform criteria to determine which patients should undergo workup as outpatients and which as inpatients. “There was a lot of selection bias that may have had nothing to do with how sick the person was,” Dr. Caplan said.

In addition, few hospitals in the United States have an outpatient TIA clinic, he noted. Most of the studies of TIA clinics that the researchers examined were conducted in Europe. “It’s easier to do [that] in Europe because of their socialized medicine,” said Dr. Caplan.

But TIA clinics should be more widespread in the U.S., he added. “Insurance companies should be willing to pay for comparable facilities, inpatient and outpatient,” he said.

The study was conducted without external funding. Dr. Zand reported no relevant financial relationships. Dr. Caplan was an investigator for TIAregistry.org, which analyzed the outcomes of treatment in TIA clinics in Europe.

A version of this article first appeared on Medscape.com.

Inpatient and outpatient treatments of transient ischemic attack (TIA) or minor ischemic stroke (mIS) yield comparable safety outcomes, new research suggests. In a meta-analysis of more than 200,000 patients with TIA or mIS, risk for subsequent stroke within 90 days was 2.1% for those treated in a TIA clinic versus 2.8% for patients treated in inpatient settings, which was not significantly different. The risk for patients treated in an emergency department was higher, at 3.5%.

“The message is that if you do the correct risk stratification and then triage patients based on their risk profile, you can safely discharge and have a timely follow-up for the patients who have low risk for a subsequent event,” said coinvestigator Ramin Zand, MD, vascular neurologist and stroke attending physician at Geisinger Health System, Danville, Pennsylvania.

The findings were published online Jan. 5 in JAMA Network Open.
 

Higher risk in EDs

There is currently no consensus on the care protocol for patients with TIA or mIS, and the rate at which these patients are hospitalized varies by region, hospital, and practitioner, the investigators noted.

Previous studies have indicated that outpatient management of certain individuals with TIA can be safe and cost-effective.

The current researchers searched for retrospective and prospective studies of adult patients that provided information about ischemic stroke after TIA or mIS. Studies that used time- and tissue-based definitions of TIA were included, as well as studies that used various definitions of mIS.

The investigators examined care provided at TIA clinics, inpatient settings (such as medical-surgical units, stroke units, or observation units), EDs, and unspecified settings. Their main aim was to compare outcomes between TIA clinics and inpatient settings.

In all, 226,683 patients (recruited between 1981 and 2018) from 71 studies were included in the meta-analysis. The studies examined 101 cohorts, 24 of which were studied prospectively. Among the 5,636 patients who received care in TIA clinics, the mean age was 65.7 years, and 50.8% of this group were men. Among the 130,139 inpatients, the mean age was 78.3 years, and 61.6% of the group were women.

Results showed no significant difference in risk for subsequent stroke between patients treated in the inpatient and outpatient settings.

Among patients treated in a TIA clinic, risk for subsequent stroke following a TIA or mIS was 0.3% within 2 days, 1.0% within 7 days, 1.3% within 30 days, and 2.1% within 90 days. Among those treated as inpatients, risk for subsequent stroke was 0.5% within 2 days, 1.2% within 7 days, 1.6% within 30 days, and 2.8% within 90 days.

Risk for subsequent stroke was higher among patients treated in the ED and in unspecified settings. At the EDs, the risk was 1.9% within 2 days, 3.4% within 7 days, 3.5% within 30 days, and 3.5% within 90 days. Among those treated in unspecified settings, the risk was 2.2% within 2 days, 3.4% within 7 days, 4.2% within 30 days, and 6.0% within 90 days.

Patients treated in the ED also had a significantly higher risk for subsequent stroke at 2 and 7 days, compared with those treated in inpatient settings and a significantly higher risk for subsequent stroke at 2, 7, and 90 days, compared with those treated in TIA clinics.
 

‘Most comprehensive look’

“This is the most comprehensive look at all the studies to try and answer this research question,” said Dr. Zand. The results were similar to what was expected, he added.

The infrastructure and resources differed among the sites at which the various studies were conducted, and the investigators adjusted for these differences as much as possible, Dr. Zand noted. A certain amount of selection bias may remain, but it does not affect the overall conclusion, he added.

“Timely outpatient care among low-risk TIA patients is both feasible and safe,” he said.

Dr. Zand noted that the findings have implications not only for patient management but also for the management of the health system. “It’s not feasible nor desirable to admit all the TIA patients, especially with the lessons that we learned from COVID, the burden on the health systems, and the fact that many hospitals are operating at full capacity right now,” he said.

The recommendation is to hospitalize high-risk patients and provide outpatient evaluation and workup to low-risk patients, he added. “This is exactly what we saw in this study,” Dr. Zand said.
 

Selection bias?

Commenting on the research, Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, noted that evaluation of patients with TIA or mIS “can be done very well as an outpatient” if clinicians have experienced personnel, the outpatient facilities to do the studies necessary, and criteria in place for deciding who to admit or not admit.

However, the decision on whether to choose an inpatient or outpatient approach for a particular patient is complicated, said Dr. Caplan, who was not involved with the research.

Clinicians must consider factors such as whether the patient is mobile, has a car, or has a significant other. The patient’s symptoms and past illnesses also influence the decision, he added.

Dr. Caplan noted that in the meta-analysis, far fewer patients were seen in the TIA clinics than were seen in the inpatient setting. In addition, none of the studies used uniform criteria to determine which patients should undergo workup as outpatients and which as inpatients. “There was a lot of selection bias that may have had nothing to do with how sick the person was,” Dr. Caplan said.

In addition, few hospitals in the United States have an outpatient TIA clinic, he noted. Most of the studies of TIA clinics that the researchers examined were conducted in Europe. “It’s easier to do [that] in Europe because of their socialized medicine,” said Dr. Caplan.

But TIA clinics should be more widespread in the U.S., he added. “Insurance companies should be willing to pay for comparable facilities, inpatient and outpatient,” he said.

The study was conducted without external funding. Dr. Zand reported no relevant financial relationships. Dr. Caplan was an investigator for TIAregistry.org, which analyzed the outcomes of treatment in TIA clinics in Europe.

A version of this article first appeared on Medscape.com.

Inpatient and outpatient treatments of transient ischemic attack (TIA) or minor ischemic stroke (mIS) yield comparable safety outcomes, new research suggests. In a meta-analysis of more than 200,000 patients with TIA or mIS, risk for subsequent stroke within 90 days was 2.1% for those treated in a TIA clinic versus 2.8% for patients treated in inpatient settings, which was not significantly different. The risk for patients treated in an emergency department was higher, at 3.5%.

“The message is that if you do the correct risk stratification and then triage patients based on their risk profile, you can safely discharge and have a timely follow-up for the patients who have low risk for a subsequent event,” said coinvestigator Ramin Zand, MD, vascular neurologist and stroke attending physician at Geisinger Health System, Danville, Pennsylvania.

The findings were published online Jan. 5 in JAMA Network Open.
 

Higher risk in EDs

There is currently no consensus on the care protocol for patients with TIA or mIS, and the rate at which these patients are hospitalized varies by region, hospital, and practitioner, the investigators noted.

Previous studies have indicated that outpatient management of certain individuals with TIA can be safe and cost-effective.

The current researchers searched for retrospective and prospective studies of adult patients that provided information about ischemic stroke after TIA or mIS. Studies that used time- and tissue-based definitions of TIA were included, as well as studies that used various definitions of mIS.

The investigators examined care provided at TIA clinics, inpatient settings (such as medical-surgical units, stroke units, or observation units), EDs, and unspecified settings. Their main aim was to compare outcomes between TIA clinics and inpatient settings.

In all, 226,683 patients (recruited between 1981 and 2018) from 71 studies were included in the meta-analysis. The studies examined 101 cohorts, 24 of which were studied prospectively. Among the 5,636 patients who received care in TIA clinics, the mean age was 65.7 years, and 50.8% of this group were men. Among the 130,139 inpatients, the mean age was 78.3 years, and 61.6% of the group were women.

Results showed no significant difference in risk for subsequent stroke between patients treated in the inpatient and outpatient settings.

Among patients treated in a TIA clinic, risk for subsequent stroke following a TIA or mIS was 0.3% within 2 days, 1.0% within 7 days, 1.3% within 30 days, and 2.1% within 90 days. Among those treated as inpatients, risk for subsequent stroke was 0.5% within 2 days, 1.2% within 7 days, 1.6% within 30 days, and 2.8% within 90 days.

Risk for subsequent stroke was higher among patients treated in the ED and in unspecified settings. At the EDs, the risk was 1.9% within 2 days, 3.4% within 7 days, 3.5% within 30 days, and 3.5% within 90 days. Among those treated in unspecified settings, the risk was 2.2% within 2 days, 3.4% within 7 days, 4.2% within 30 days, and 6.0% within 90 days.

Patients treated in the ED also had a significantly higher risk for subsequent stroke at 2 and 7 days, compared with those treated in inpatient settings and a significantly higher risk for subsequent stroke at 2, 7, and 90 days, compared with those treated in TIA clinics.
 

‘Most comprehensive look’

“This is the most comprehensive look at all the studies to try and answer this research question,” said Dr. Zand. The results were similar to what was expected, he added.

The infrastructure and resources differed among the sites at which the various studies were conducted, and the investigators adjusted for these differences as much as possible, Dr. Zand noted. A certain amount of selection bias may remain, but it does not affect the overall conclusion, he added.

“Timely outpatient care among low-risk TIA patients is both feasible and safe,” he said.

Dr. Zand noted that the findings have implications not only for patient management but also for the management of the health system. “It’s not feasible nor desirable to admit all the TIA patients, especially with the lessons that we learned from COVID, the burden on the health systems, and the fact that many hospitals are operating at full capacity right now,” he said.

The recommendation is to hospitalize high-risk patients and provide outpatient evaluation and workup to low-risk patients, he added. “This is exactly what we saw in this study,” Dr. Zand said.
 

Selection bias?

Commenting on the research, Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, noted that evaluation of patients with TIA or mIS “can be done very well as an outpatient” if clinicians have experienced personnel, the outpatient facilities to do the studies necessary, and criteria in place for deciding who to admit or not admit.

However, the decision on whether to choose an inpatient or outpatient approach for a particular patient is complicated, said Dr. Caplan, who was not involved with the research.

Clinicians must consider factors such as whether the patient is mobile, has a car, or has a significant other. The patient’s symptoms and past illnesses also influence the decision, he added.

Dr. Caplan noted that in the meta-analysis, far fewer patients were seen in the TIA clinics than were seen in the inpatient setting. In addition, none of the studies used uniform criteria to determine which patients should undergo workup as outpatients and which as inpatients. “There was a lot of selection bias that may have had nothing to do with how sick the person was,” Dr. Caplan said.

In addition, few hospitals in the United States have an outpatient TIA clinic, he noted. Most of the studies of TIA clinics that the researchers examined were conducted in Europe. “It’s easier to do [that] in Europe because of their socialized medicine,” said Dr. Caplan.

But TIA clinics should be more widespread in the U.S., he added. “Insurance companies should be willing to pay for comparable facilities, inpatient and outpatient,” he said.

The study was conducted without external funding. Dr. Zand reported no relevant financial relationships. Dr. Caplan was an investigator for TIAregistry.org, which analyzed the outcomes of treatment in TIA clinics in Europe.

A version of this article first appeared on Medscape.com.

The risk of myocarditis after immunization with mRNA-based vaccines against SARS-CoV-2 raised concerns when it came to light in early 2021. But as report after report showed such cases to be rare and usually mild and self-limited, focus has turned to the “how and why.”  

The mechanism linking the BNT162b2 (Pfizer-BioNTech) and especially mRNA-1273 (Moderna) vaccines to the occurrence of myocarditis is unclear for now, but one potential driver may be tied to a peculiarity that became apparent early: It occurs overwhelmingly in younger males, from 16 to perhaps 40 or 50 years of age. Excess risk has not been consistently seen among women, girls, and older men.

peterschreiber_media/iStock/Getty Images

That observation has led to speculation that higher testosterone levels in adolescent boys and young men may somehow promote the adverse vaccine effect, whereas greater levels of estrogen among girls and women in the same age range may be cardioprotective.
 

Unlikely, brief, and ‘benign’

“Most of the myocarditis is benign, by which I mean that maybe the patients are admitted due to chest pain, but without reduction in ventricular function,” Enrico Ammirati, MD, PhD, a myocarditis expert at De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, said in an interview.

In a Nov. 14 address on this topic at the annual scientific sessions of the American Heart Association, Dror Mevorach, MD, described the typical case presentation as “mild” and one that clears in fairly short order based on resolution of “clinical symptoms, inflammatory markers and troponin decline, EKG normalization, echo normalization, and a relatively short length of hospital stay.”

Dr. Mevorach, of Hadassah Hebrew University Medical Center, Jerusalem, subsequently published the findings in a report in the New England Journal of Medicine that described 136 confirmed myocarditis cases among more than 5 million people in Israel immunized with the Pfizer-BioNTech vaccine. Myocarditis was considered “mild” in 129 cases, or 95%.

And the risk is tiny, compared with myocarditis from infection by SARS-CoV-2, not to mention the possibility of nasty clinical COVID-19 complications such as pneumonia and pulmonary embolism, Dr. Mevorach observed.

Many other reports agree that the incidence is minimal, especially given the rewards of vaccination. In a separate NEJM publication in September 2021 – from Noam Barda, MD, Clalit (Israel) Research Institute, and colleagues on 1.7 million people in that country, about half unvaccinated and half given the Pfizer-BioNTech vaccine – there were an estimated 2.7 cases of  myocarditis per 100,000 vaccinated persons. There were also 11 cases of myocarditis per 100,000 persons who were positive for SARS-CoV-2 infection.

And in a recent case series of vaccinated people aged 16 or older, the myocarditis rate after a first or second Pfizer-BioNTech or Moderna injection was estimated at 1 or fewer per 100,000. The corresponding estimate was 4 such cases per 100,000 after a positive SARS-CoV-2 test among the same population, notes a report published Dec.14, 2021, in Nature Medicine.

In general, “the risk of any kind of cardiac injury is vastly lower with a vaccine than it is with the actual viral infection,” Leslie T. Cooper Jr., MD, a myocarditis expert and clinical trialist at the Mayo Clinic, Jacksonville, Fla., said in an interview. With the mRNA-based vaccines, “we do not have any conceivable danger signal that would outweigh the benefit of vaccination.”
 

Males of a certain age

Evidence that such myocarditis predominates in young adult men and adolescent boys, especially following a second vaccine dose, is remarkably consistent.

The risk was elevated only among mRNA-based vaccine recipients who were younger than 40 in the recent Nature Medicine analysis. Among that group, estimates after a second dose numbered fewer than 1 case per 100,000 for Pfizer-BioNTech and 1.5 per 100,000 for Moderna.

In a third analysis from Israel – also in NEJM, from Guy Witberg, MD, Rabin Medical Center, Petah Tikva, and colleagues, based on 2.5 million people aged 16 and older with at least one Pfizer-BioNTech injection – 2.1 cases per 100,000 were estimated overall, but the number rose to 10.7 per 100,000 among those aged 16-29 years.

In Dr. Mevorach’s NEJM report, estimates after a second Pfizer-BioNTech vaccine dose were 1 per 26,000 males versus 1 in 218,000 females, compared with 1 myocarditis case in 10,857 persons among “the general unvaccinated population.”

Most recipients of a first vaccine dose were younger than 50, and 16- to 29-year-olds accounted for most who completed two doses, noted Dr. Mevorach. Younger males bore the brunt of any myocarditis: the estimated prevalence after a second dose among males aged 16-19 was 1 per 6,637, compared with 1 per 99,853 females in the same age range, the group reported.

In the BMJ report, based on about 5 million people 12 years of age or older in Denmark, the estimated rates of myocarditis or pericarditis associated with Moderna immunization were 2 per 100,000 among women but 6.3 per 100,000 for men. The incidence and sex difference was much lower among those getting the Pfizer-BioNTech vaccine: 1.3 per 100,000 and 1.5 per 100,000 in women and men, respectively.
 

Sex hormones may be key

The predominance of vaccine-associated myocarditis among adolescent and young adult males is probably more about the myocarditis itself than the vaccines, observed Biykem Bozkurt, MD, PhD, who has been studying COVID-related myocarditis at Baylor College of Medicine, Houston.

Male sex historically is associated in both epidemiologic studies and experimental models with a greater propensity for most any form of myocarditis, Dr. Bozkurt said in an interview. Given that males aged 16-19 or so appear to be at highest risk of myocarditis as a complication of SARS-CoV-2 vaccination, the mechanism may well be related to sex hormones.  

“Therefore, testosterone is implicated as a player in their higher risk of inflammation and injury and lack of adaptive response in terms of healing, and in terms of prevention of injury,” Dr. Bozkurt said. For its part, estrogen inhibits proinflammatory processes and, in particular, “blunts cell-mediated immune responses.”

“We don’t know the mechanism, but a theory that attributes a protective role to estrogen, or a risk associated with testosterone, is reasonable. It makes sense, at least based on epidemiological data,” Dr. Ammirati agreed. Still, “we do not have any direct evidence in human beings.”

Sex-associated differences in experimental myocarditis have been reported in the journals for at least 70 years, but “the testosterone literature and the estrogen literature have not been evaluated in detail in vaccine-associated myocarditis,” Dr. Cooper said.

Most myocarditis in the laboratory is viral, Dr. Cooper observed, and “the links between testosterone, viruses, and inflammation have been pretty well worked out, I would say, if you’re a mouse. If you’re a human, I think it’s still a bit uncertain.”

Were it to apply in humans, greater testosterone levels might independently promote myocarditis, “and if estrogen is cardioprotective, it would be another mechanism,” Dr. Cooper said. “That would translate to slight male predominance in most kinds of myocarditis.”

In males, compared with females, “the heart can be more vulnerable to events such as arrhythmias or to immune-mediated phenomena. So, probably there is also higher vulnerability to myocarditis in men,” Dr. Ammirati noted.

Male predominance in vaccine-related myocarditis is provocative, so it’s worth considering whether testosterone is part of the mechanism as well as the possibility of estrogen cardioprotection, Dr. Ammirati said. But given limitations of the animal models, “we don’t really have robust data to support any part of that.”

Although myocarditis is in some way immune mediated, “and hormones can modulate the response,” the mechanism has to be more than just sex hormones, he said. “They probably cannot explain the specificity for the heart. It’s not a systemic response, it’s an organ-specific response.”
 

Modulation of immune responses

Details about the immune processes underlying mRNA-vaccine myocarditis, hormone modulated or not, have been elusive. The complication doesn’t resemble serum sickness, nor does it seem to be a reaction to infection by other cardiotropic viruses, such as coxsackie virus B, a cause of viral myocarditis, Dr. Bozkurt said. The latter had been a compelling possibility because such hypersensitivity to smallpox vaccination is well recognized.

“We don’t know the mechanism, that’s the short answer. But there are many hypotheses,” she said. One candidate widely proposed in the literature: autoantibodies driven by molecular mimicry between the SARS-CoV-2 spike protein targeted by the mRNA vaccines and a structurally similar myocardial protein, possibly alpha-myosin, noted Dr. Bozkurt and colleagues in a recent publication.

But elevations in specific “antiheart antibodies” have not been documented in recipients of the two mRNA-based vaccines, said Dr. Cooper. “So, I would say that – although molecular mimicry is a well-established mechanism of, for example, rheumatic carditis after a streptococcal A infection – that has not been demonstrated yet for COVID-19 mRNA vaccination–related myocarditis.”

“We probably won’t know, ever, with a huge level of certainty, the exact mechanisms,” Dr. Cooper added. There is no animal model for vaccine-induced myocarditis, and “We’re still talking very, very small numbers of patients. The vast majority of them recover,” and so don’t generally provide mechanistic clues.  
 

Prospects for younger children

Vaccination against SARS-CoV-2 has now been authorized by the Centers for Disease Control and Prevention for kids as young as 5-11 years, using the Pfizer-BioNTech vaccine. Experience so far suggests the immunization is safe in that age group with negligible risk of myocarditis or other complications. But with prospects of possible authorization in children younger than 5, should myocarditis be a concern for them?

Probably not, if the complication is driven primarily by sex hormones, Dr. Cooper proposed. “One would predict that before puberty you would have a lower – much, much lower – rate of myocarditis in males than you would in the 16- to 19-year-old range, and that it would be roughly equal to females.” Dr. Ammirati and Dr. Bozkurt largely agreed.

It remains to be seen whether the vaccine-related myocarditis risk applies to children younger than 12, “but I doubt it. I think it’s going to be puberty-related,” Dr. Bozkurt said. Still, “I don’t want to hypothesize without data.”

A version of this article first appeared on Medscape.com.

The risk of myocarditis after immunization with mRNA-based vaccines against SARS-CoV-2 raised concerns when it came to light in early 2021. But as report after report showed such cases to be rare and usually mild and self-limited, focus has turned to the “how and why.”  

The mechanism linking the BNT162b2 (Pfizer-BioNTech) and especially mRNA-1273 (Moderna) vaccines to the occurrence of myocarditis is unclear for now, but one potential driver may be tied to a peculiarity that became apparent early: It occurs overwhelmingly in younger males, from 16 to perhaps 40 or 50 years of age. Excess risk has not been consistently seen among women, girls, and older men.

peterschreiber_media/iStock/Getty Images

That observation has led to speculation that higher testosterone levels in adolescent boys and young men may somehow promote the adverse vaccine effect, whereas greater levels of estrogen among girls and women in the same age range may be cardioprotective.
 

Unlikely, brief, and ‘benign’

“Most of the myocarditis is benign, by which I mean that maybe the patients are admitted due to chest pain, but without reduction in ventricular function,” Enrico Ammirati, MD, PhD, a myocarditis expert at De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, said in an interview.

In a Nov. 14 address on this topic at the annual scientific sessions of the American Heart Association, Dror Mevorach, MD, described the typical case presentation as “mild” and one that clears in fairly short order based on resolution of “clinical symptoms, inflammatory markers and troponin decline, EKG normalization, echo normalization, and a relatively short length of hospital stay.”

Dr. Mevorach, of Hadassah Hebrew University Medical Center, Jerusalem, subsequently published the findings in a report in the New England Journal of Medicine that described 136 confirmed myocarditis cases among more than 5 million people in Israel immunized with the Pfizer-BioNTech vaccine. Myocarditis was considered “mild” in 129 cases, or 95%.

And the risk is tiny, compared with myocarditis from infection by SARS-CoV-2, not to mention the possibility of nasty clinical COVID-19 complications such as pneumonia and pulmonary embolism, Dr. Mevorach observed.

Many other reports agree that the incidence is minimal, especially given the rewards of vaccination. In a separate NEJM publication in September 2021 – from Noam Barda, MD, Clalit (Israel) Research Institute, and colleagues on 1.7 million people in that country, about half unvaccinated and half given the Pfizer-BioNTech vaccine – there were an estimated 2.7 cases of  myocarditis per 100,000 vaccinated persons. There were also 11 cases of myocarditis per 100,000 persons who were positive for SARS-CoV-2 infection.

And in a recent case series of vaccinated people aged 16 or older, the myocarditis rate after a first or second Pfizer-BioNTech or Moderna injection was estimated at 1 or fewer per 100,000. The corresponding estimate was 4 such cases per 100,000 after a positive SARS-CoV-2 test among the same population, notes a report published Dec.14, 2021, in Nature Medicine.

In general, “the risk of any kind of cardiac injury is vastly lower with a vaccine than it is with the actual viral infection,” Leslie T. Cooper Jr., MD, a myocarditis expert and clinical trialist at the Mayo Clinic, Jacksonville, Fla., said in an interview. With the mRNA-based vaccines, “we do not have any conceivable danger signal that would outweigh the benefit of vaccination.”
 

Males of a certain age

Evidence that such myocarditis predominates in young adult men and adolescent boys, especially following a second vaccine dose, is remarkably consistent.

The risk was elevated only among mRNA-based vaccine recipients who were younger than 40 in the recent Nature Medicine analysis. Among that group, estimates after a second dose numbered fewer than 1 case per 100,000 for Pfizer-BioNTech and 1.5 per 100,000 for Moderna.

In a third analysis from Israel – also in NEJM, from Guy Witberg, MD, Rabin Medical Center, Petah Tikva, and colleagues, based on 2.5 million people aged 16 and older with at least one Pfizer-BioNTech injection – 2.1 cases per 100,000 were estimated overall, but the number rose to 10.7 per 100,000 among those aged 16-29 years.

In Dr. Mevorach’s NEJM report, estimates after a second Pfizer-BioNTech vaccine dose were 1 per 26,000 males versus 1 in 218,000 females, compared with 1 myocarditis case in 10,857 persons among “the general unvaccinated population.”

Most recipients of a first vaccine dose were younger than 50, and 16- to 29-year-olds accounted for most who completed two doses, noted Dr. Mevorach. Younger males bore the brunt of any myocarditis: the estimated prevalence after a second dose among males aged 16-19 was 1 per 6,637, compared with 1 per 99,853 females in the same age range, the group reported.

In the BMJ report, based on about 5 million people 12 years of age or older in Denmark, the estimated rates of myocarditis or pericarditis associated with Moderna immunization were 2 per 100,000 among women but 6.3 per 100,000 for men. The incidence and sex difference was much lower among those getting the Pfizer-BioNTech vaccine: 1.3 per 100,000 and 1.5 per 100,000 in women and men, respectively.
 

Sex hormones may be key

The predominance of vaccine-associated myocarditis among adolescent and young adult males is probably more about the myocarditis itself than the vaccines, observed Biykem Bozkurt, MD, PhD, who has been studying COVID-related myocarditis at Baylor College of Medicine, Houston.

Male sex historically is associated in both epidemiologic studies and experimental models with a greater propensity for most any form of myocarditis, Dr. Bozkurt said in an interview. Given that males aged 16-19 or so appear to be at highest risk of myocarditis as a complication of SARS-CoV-2 vaccination, the mechanism may well be related to sex hormones.  

“Therefore, testosterone is implicated as a player in their higher risk of inflammation and injury and lack of adaptive response in terms of healing, and in terms of prevention of injury,” Dr. Bozkurt said. For its part, estrogen inhibits proinflammatory processes and, in particular, “blunts cell-mediated immune responses.”

“We don’t know the mechanism, but a theory that attributes a protective role to estrogen, or a risk associated with testosterone, is reasonable. It makes sense, at least based on epidemiological data,” Dr. Ammirati agreed. Still, “we do not have any direct evidence in human beings.”

Sex-associated differences in experimental myocarditis have been reported in the journals for at least 70 years, but “the testosterone literature and the estrogen literature have not been evaluated in detail in vaccine-associated myocarditis,” Dr. Cooper said.

Most myocarditis in the laboratory is viral, Dr. Cooper observed, and “the links between testosterone, viruses, and inflammation have been pretty well worked out, I would say, if you’re a mouse. If you’re a human, I think it’s still a bit uncertain.”

Were it to apply in humans, greater testosterone levels might independently promote myocarditis, “and if estrogen is cardioprotective, it would be another mechanism,” Dr. Cooper said. “That would translate to slight male predominance in most kinds of myocarditis.”

In males, compared with females, “the heart can be more vulnerable to events such as arrhythmias or to immune-mediated phenomena. So, probably there is also higher vulnerability to myocarditis in men,” Dr. Ammirati noted.

Male predominance in vaccine-related myocarditis is provocative, so it’s worth considering whether testosterone is part of the mechanism as well as the possibility of estrogen cardioprotection, Dr. Ammirati said. But given limitations of the animal models, “we don’t really have robust data to support any part of that.”

Although myocarditis is in some way immune mediated, “and hormones can modulate the response,” the mechanism has to be more than just sex hormones, he said. “They probably cannot explain the specificity for the heart. It’s not a systemic response, it’s an organ-specific response.”
 

Modulation of immune responses

Details about the immune processes underlying mRNA-vaccine myocarditis, hormone modulated or not, have been elusive. The complication doesn’t resemble serum sickness, nor does it seem to be a reaction to infection by other cardiotropic viruses, such as coxsackie virus B, a cause of viral myocarditis, Dr. Bozkurt said. The latter had been a compelling possibility because such hypersensitivity to smallpox vaccination is well recognized.

“We don’t know the mechanism, that’s the short answer. But there are many hypotheses,” she said. One candidate widely proposed in the literature: autoantibodies driven by molecular mimicry between the SARS-CoV-2 spike protein targeted by the mRNA vaccines and a structurally similar myocardial protein, possibly alpha-myosin, noted Dr. Bozkurt and colleagues in a recent publication.

But elevations in specific “antiheart antibodies” have not been documented in recipients of the two mRNA-based vaccines, said Dr. Cooper. “So, I would say that – although molecular mimicry is a well-established mechanism of, for example, rheumatic carditis after a streptococcal A infection – that has not been demonstrated yet for COVID-19 mRNA vaccination–related myocarditis.”

“We probably won’t know, ever, with a huge level of certainty, the exact mechanisms,” Dr. Cooper added. There is no animal model for vaccine-induced myocarditis, and “We’re still talking very, very small numbers of patients. The vast majority of them recover,” and so don’t generally provide mechanistic clues.  
 

Prospects for younger children

Vaccination against SARS-CoV-2 has now been authorized by the Centers for Disease Control and Prevention for kids as young as 5-11 years, using the Pfizer-BioNTech vaccine. Experience so far suggests the immunization is safe in that age group with negligible risk of myocarditis or other complications. But with prospects of possible authorization in children younger than 5, should myocarditis be a concern for them?

Probably not, if the complication is driven primarily by sex hormones, Dr. Cooper proposed. “One would predict that before puberty you would have a lower – much, much lower – rate of myocarditis in males than you would in the 16- to 19-year-old range, and that it would be roughly equal to females.” Dr. Ammirati and Dr. Bozkurt largely agreed.

It remains to be seen whether the vaccine-related myocarditis risk applies to children younger than 12, “but I doubt it. I think it’s going to be puberty-related,” Dr. Bozkurt said. Still, “I don’t want to hypothesize without data.”

A version of this article first appeared on Medscape.com.

The risk of myocarditis after immunization with mRNA-based vaccines against SARS-CoV-2 raised concerns when it came to light in early 2021. But as report after report showed such cases to be rare and usually mild and self-limited, focus has turned to the “how and why.”  

The mechanism linking the BNT162b2 (Pfizer-BioNTech) and especially mRNA-1273 (Moderna) vaccines to the occurrence of myocarditis is unclear for now, but one potential driver may be tied to a peculiarity that became apparent early: It occurs overwhelmingly in younger males, from 16 to perhaps 40 or 50 years of age. Excess risk has not been consistently seen among women, girls, and older men.

peterschreiber_media/iStock/Getty Images

That observation has led to speculation that higher testosterone levels in adolescent boys and young men may somehow promote the adverse vaccine effect, whereas greater levels of estrogen among girls and women in the same age range may be cardioprotective.
 

Unlikely, brief, and ‘benign’

“Most of the myocarditis is benign, by which I mean that maybe the patients are admitted due to chest pain, but without reduction in ventricular function,” Enrico Ammirati, MD, PhD, a myocarditis expert at De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, said in an interview.

In a Nov. 14 address on this topic at the annual scientific sessions of the American Heart Association, Dror Mevorach, MD, described the typical case presentation as “mild” and one that clears in fairly short order based on resolution of “clinical symptoms, inflammatory markers and troponin decline, EKG normalization, echo normalization, and a relatively short length of hospital stay.”

Dr. Mevorach, of Hadassah Hebrew University Medical Center, Jerusalem, subsequently published the findings in a report in the New England Journal of Medicine that described 136 confirmed myocarditis cases among more than 5 million people in Israel immunized with the Pfizer-BioNTech vaccine. Myocarditis was considered “mild” in 129 cases, or 95%.

And the risk is tiny, compared with myocarditis from infection by SARS-CoV-2, not to mention the possibility of nasty clinical COVID-19 complications such as pneumonia and pulmonary embolism, Dr. Mevorach observed.

Many other reports agree that the incidence is minimal, especially given the rewards of vaccination. In a separate NEJM publication in September 2021 – from Noam Barda, MD, Clalit (Israel) Research Institute, and colleagues on 1.7 million people in that country, about half unvaccinated and half given the Pfizer-BioNTech vaccine – there were an estimated 2.7 cases of  myocarditis per 100,000 vaccinated persons. There were also 11 cases of myocarditis per 100,000 persons who were positive for SARS-CoV-2 infection.

And in a recent case series of vaccinated people aged 16 or older, the myocarditis rate after a first or second Pfizer-BioNTech or Moderna injection was estimated at 1 or fewer per 100,000. The corresponding estimate was 4 such cases per 100,000 after a positive SARS-CoV-2 test among the same population, notes a report published Dec.14, 2021, in Nature Medicine.

In general, “the risk of any kind of cardiac injury is vastly lower with a vaccine than it is with the actual viral infection,” Leslie T. Cooper Jr., MD, a myocarditis expert and clinical trialist at the Mayo Clinic, Jacksonville, Fla., said in an interview. With the mRNA-based vaccines, “we do not have any conceivable danger signal that would outweigh the benefit of vaccination.”
 

Males of a certain age

Evidence that such myocarditis predominates in young adult men and adolescent boys, especially following a second vaccine dose, is remarkably consistent.

The risk was elevated only among mRNA-based vaccine recipients who were younger than 40 in the recent Nature Medicine analysis. Among that group, estimates after a second dose numbered fewer than 1 case per 100,000 for Pfizer-BioNTech and 1.5 per 100,000 for Moderna.

In a third analysis from Israel – also in NEJM, from Guy Witberg, MD, Rabin Medical Center, Petah Tikva, and colleagues, based on 2.5 million people aged 16 and older with at least one Pfizer-BioNTech injection – 2.1 cases per 100,000 were estimated overall, but the number rose to 10.7 per 100,000 among those aged 16-29 years.

In Dr. Mevorach’s NEJM report, estimates after a second Pfizer-BioNTech vaccine dose were 1 per 26,000 males versus 1 in 218,000 females, compared with 1 myocarditis case in 10,857 persons among “the general unvaccinated population.”

Most recipients of a first vaccine dose were younger than 50, and 16- to 29-year-olds accounted for most who completed two doses, noted Dr. Mevorach. Younger males bore the brunt of any myocarditis: the estimated prevalence after a second dose among males aged 16-19 was 1 per 6,637, compared with 1 per 99,853 females in the same age range, the group reported.

In the BMJ report, based on about 5 million people 12 years of age or older in Denmark, the estimated rates of myocarditis or pericarditis associated with Moderna immunization were 2 per 100,000 among women but 6.3 per 100,000 for men. The incidence and sex difference was much lower among those getting the Pfizer-BioNTech vaccine: 1.3 per 100,000 and 1.5 per 100,000 in women and men, respectively.
 

Sex hormones may be key

The predominance of vaccine-associated myocarditis among adolescent and young adult males is probably more about the myocarditis itself than the vaccines, observed Biykem Bozkurt, MD, PhD, who has been studying COVID-related myocarditis at Baylor College of Medicine, Houston.

Male sex historically is associated in both epidemiologic studies and experimental models with a greater propensity for most any form of myocarditis, Dr. Bozkurt said in an interview. Given that males aged 16-19 or so appear to be at highest risk of myocarditis as a complication of SARS-CoV-2 vaccination, the mechanism may well be related to sex hormones.  

“Therefore, testosterone is implicated as a player in their higher risk of inflammation and injury and lack of adaptive response in terms of healing, and in terms of prevention of injury,” Dr. Bozkurt said. For its part, estrogen inhibits proinflammatory processes and, in particular, “blunts cell-mediated immune responses.”

“We don’t know the mechanism, but a theory that attributes a protective role to estrogen, or a risk associated with testosterone, is reasonable. It makes sense, at least based on epidemiological data,” Dr. Ammirati agreed. Still, “we do not have any direct evidence in human beings.”

Sex-associated differences in experimental myocarditis have been reported in the journals for at least 70 years, but “the testosterone literature and the estrogen literature have not been evaluated in detail in vaccine-associated myocarditis,” Dr. Cooper said.

Most myocarditis in the laboratory is viral, Dr. Cooper observed, and “the links between testosterone, viruses, and inflammation have been pretty well worked out, I would say, if you’re a mouse. If you’re a human, I think it’s still a bit uncertain.”

Were it to apply in humans, greater testosterone levels might independently promote myocarditis, “and if estrogen is cardioprotective, it would be another mechanism,” Dr. Cooper said. “That would translate to slight male predominance in most kinds of myocarditis.”

In males, compared with females, “the heart can be more vulnerable to events such as arrhythmias or to immune-mediated phenomena. So, probably there is also higher vulnerability to myocarditis in men,” Dr. Ammirati noted.

Male predominance in vaccine-related myocarditis is provocative, so it’s worth considering whether testosterone is part of the mechanism as well as the possibility of estrogen cardioprotection, Dr. Ammirati said. But given limitations of the animal models, “we don’t really have robust data to support any part of that.”

Although myocarditis is in some way immune mediated, “and hormones can modulate the response,” the mechanism has to be more than just sex hormones, he said. “They probably cannot explain the specificity for the heart. It’s not a systemic response, it’s an organ-specific response.”
 

Modulation of immune responses

Details about the immune processes underlying mRNA-vaccine myocarditis, hormone modulated or not, have been elusive. The complication doesn’t resemble serum sickness, nor does it seem to be a reaction to infection by other cardiotropic viruses, such as coxsackie virus B, a cause of viral myocarditis, Dr. Bozkurt said. The latter had been a compelling possibility because such hypersensitivity to smallpox vaccination is well recognized.

“We don’t know the mechanism, that’s the short answer. But there are many hypotheses,” she said. One candidate widely proposed in the literature: autoantibodies driven by molecular mimicry between the SARS-CoV-2 spike protein targeted by the mRNA vaccines and a structurally similar myocardial protein, possibly alpha-myosin, noted Dr. Bozkurt and colleagues in a recent publication.

But elevations in specific “antiheart antibodies” have not been documented in recipients of the two mRNA-based vaccines, said Dr. Cooper. “So, I would say that – although molecular mimicry is a well-established mechanism of, for example, rheumatic carditis after a streptococcal A infection – that has not been demonstrated yet for COVID-19 mRNA vaccination–related myocarditis.”

“We probably won’t know, ever, with a huge level of certainty, the exact mechanisms,” Dr. Cooper added. There is no animal model for vaccine-induced myocarditis, and “We’re still talking very, very small numbers of patients. The vast majority of them recover,” and so don’t generally provide mechanistic clues.  
 

Prospects for younger children

Vaccination against SARS-CoV-2 has now been authorized by the Centers for Disease Control and Prevention for kids as young as 5-11 years, using the Pfizer-BioNTech vaccine. Experience so far suggests the immunization is safe in that age group with negligible risk of myocarditis or other complications. But with prospects of possible authorization in children younger than 5, should myocarditis be a concern for them?

Probably not, if the complication is driven primarily by sex hormones, Dr. Cooper proposed. “One would predict that before puberty you would have a lower – much, much lower – rate of myocarditis in males than you would in the 16- to 19-year-old range, and that it would be roughly equal to females.” Dr. Ammirati and Dr. Bozkurt largely agreed.

It remains to be seen whether the vaccine-related myocarditis risk applies to children younger than 12, “but I doubt it. I think it’s going to be puberty-related,” Dr. Bozkurt said. Still, “I don’t want to hypothesize without data.”

A version of this article first appeared on Medscape.com.